“Oh my god. It made me lose weight,” said a 61-year-old woman.

“Not craving food is great,” reported a 65-year-old man.

“I didn’t feel sluggish at work,” said a 56-year-old woman.

“Before the trial, I didn’t have any hope,” recalled a 71-year-old man.

Those comments were made by participants in two trials—SURPASS-2 and SURPASS-3—that gave a new drug called tirzepatide (sold by Eli Lilly as Mounjaro) to people with type 2 diabetes. (All the drug trials cited here were funded by the drugs’ manufacturers.)

In May, the Food and Drug Administration approved tirzepatide—which patients inject under their skin weekly—to treat type 2 diabetes, because in clinical trials it cut hemoglobin A1c levels (a long-term measure of blood sugar) even more than taking insulin.

The FDA has not yet approved tirzepatide for weight loss. But that may soon happen.

How much weight do people lose with tirzepatide?

“People have achieved an astounding amount of weight loss with tirzepatide,” says Julie Ingelfinger, professor of pediatrics at Harvard Medical School, who co-authored an editorial accompanying the recent SURMOUNT-1 trial on the impact of the drug on 2,539 people without diabetes.

After roughly 18 months, the average participant who got 10 or 15 milligrams of tirzepatide per week lost roughly 20 percent of their initial weight. That was about 45 pounds for average participants, who started the trial at around 230 pounds. Placebo takers lost 3 percent of their initial weight. (All participants were also counseled to cut 500 calories a day and do at least 150 minutes of exercise a week.)

“The magnitude of weight loss with tirzepatide was similar to what patients can expect with gastric bypass surgery,” notes Ingelfinger. What’s more, the drug lowered blood pressure, LDL (“bad”) cholesterol, fasting insulin, and hemoglobin A1c.

And tirzepatide isn’t alone.

How much weight do people lose with semaglutide?

In 2021, the FDA approved semaglutide (sold as Wegovy) for weight loss. (It’s also sold as Ozempic to treat type 2 diabetes.) Both drugs, made by Novo Nordisk, are injected weekly.

In STEP 1, the largest clinical trial, semaglutide takers lost, on average, 15 percent of their initial weight, or about 35 pounds, after 68 weeks. Placebo takers lost only 2 percent.

(Again, all participants were advised to cut 500 calories a day and do 150 minutes of exercise each week.)

The drug is pricey—about $1,350 per month—and neither Medicare nor many insurance plans cover the cost...though they typically cover Ozempic if patients have type 2 diabetes.

How semaglutide leads to weight loss

The drug, which was approved to treat type 2 diabetes in 2017, is a version of glucagon-like peptide-1 (GLP-1) that stays active longer.

“GLP-1 is a naturally occurring hormone that is released by the cells in the small intestine when food, particularly carbo­hydrates, hits the stomach,” explains Thomas Wadden, professor of psychology at the University of Penn­sylvania Perelman School of Medicine. (Wadden led the STEP 3 trial and receives advisory board fees from Novo Nordisk, along with grant support paid to the University of Pennsylvania.)

GLP-1 acts via three pathways.

“First, it signals the pancreas to release insulin to pick up the glucose that’s coming in,” says Wadden. “Second, it slows gastric emptying, which leads to greater feelings of fullness. And third, it hits a part of the brain that stimulates fullness, so people feel full earlier when they’re eating and don’t eat as much.”

Naturally occurring GLP-1 is active for only about two to three minutes after you eat.

In contrast, half of a semaglutide injection is still in your system after a week, notes Wadden.

“So people feel greater fullness and less hunger around the clock. They’re less responsive to cues in our environment that are saying, 'It’s time to have a large serving of ice cream’ or whatever. People seem to be less vulnerable to the toxic food environment.”

How tirzepatide leads to weight loss

It combines longer-acting versions of both GLP-1 and glucose-dependent insulino­tropic peptide (GIP), another naturally occurring hormone.

“GIP stimulates insulin release when blood sugar levels are high, so it improves glucose tolerance,” explains Ingelfinger. “GIP also acts on the brain and seems to regulate fat tissue storage.”

Tirzepatide not only leads to more weight loss than semaglutide. “In the SURPASS-2 trial, it was superior to semaglutide at lowering long-term blood sugar levels,” says Ingelfinger. “So it appears to be a very promising drug.”

Older weight-loss drugs

Novo Nordisk’s liraglutide, sold as Saxenda, is a version of GLP-1 that doesn’t last as long as semaglutide or tirzepatide. When inject­ed daily for 56 weeks, it led to an 8 percent weight loss vs. 3 percent in placebo takers.

And people who take other weight-loss drugs—like Alli, Xenical, Contrave, or Qsymia—typically lose only 4 to 8 percent of their weight compared to placebo takers.

What are the risks of semaglutide or tirzepatide for weight loss?

Among the possible downsides of taking tirzepatide or semaglutide: an increased risk of thyroid tumors, GI symptoms, and gallstones. 

Thyroid tumors

Both drugs increased the risk of thyroid tumors in rat studies. It’s not clear if they do the same in humans.

GI symptoms

“At first, about 45 to 50 percent of people taking semaglutide experience nausea and about 25 percent experience vomiting,” says Wadden. “Constipation and diarrhea also occur.” (The same symptoms are common with tirzepatide.)

Ramping up the dose over four to five months can help. “Chewing food more thoroughly, eating smaller, more frequent meals, and drinking more water can help with nausea if it’s persistent,” adds Wadden.

Gallstones

“About 3 percent of people on semaglutide will develop gallstones or need to have a gallbladder removed,” says Wadden. (Those complications also occur with tirzepatide.)

That’s partly because the GLP-1 drugs make the gallbladder empty more slowly. But it may also be due to the weight loss itself, since gallstones also occur more often in people who undergo gastric bypass surgery.

Is weight loss from semaglutide or tirzepatide permanent?

Another downside: If you stop the drugs, the weight starts to come back.

In the STEP 4 trial, for example, people with obesity lost an average of 24 pounds (11 percent of their initial weight) after 20 weeks on semaglutide. Those who were then randomly assigned to keep taking the drug for 48 more weeks lost another 16 pounds, while those who were switched to a placebo for those 48 weeks gained 13 pounds.

“Some people would say these drugs are a failure because if you stop taking them, you regain the weight,” says Wadden. “But I’m on medications for high blood pressure and high cholesterol. If I stop taking those medications, my cholesterol and blood pressure will go up.”

What are the unknowns?

“Nobody knows what it would be like to be on tirzepatide or semaglutide for five or 10 years,” says Ingelfinger. “Are we going to see any of the severe side effects that we saw with weight loss drugs that were pulled off the market in recent years?”

For example, Pondimin and Redux damaged heart valves, Belviq raised the risk of cancer, and Meridia increased the risk of stroke.

Despite the unknowns, Ingelfinger is optimistic about the new drugs’ potential.

“If longer-term studies show that these drugs are effective and if concerning adverse events don’t emerge over time, they may really be game changers.”