It’s possible that tirzepatide is slightly more effective because it’s a dual receptor agonist. In addition to GLP-1, it also activates receptors of GIP, another hormone involved in regulating blood sugar and appetite. But McGuire says GIP isn’t well understood, and it’s not clear whether the addition of GIP is driving the increased weight loss or if tirzepatide is just better at activating GLP-1. “We just don’t have a way to unravel that biology right now,” he says.
That hasn’t stopped pharma companies from pursuing GIP as a target. Viking Pharmaceuticals is also developing a drug that activates both the GLP-1 and GIP receptors. The San Diego company is testing both an injectable and pill form. In a trial of the injectable version, participants lost nearly 15 percent of their weight over 13 weeks. And data released in March from an early-stage trial showed that people who took Viking’s daily pill version lost around 5 percent of their weight on average in just a month.
Novo Nordisk, Eli Lilly, and Pfizer are all working on their own GLP-1 pills. Some patients may prefer taking a daily pill over a weekly injection. Pills are also easier to manufacture than the injector pens used to administer Wegovy and Zepbound. The pens also have to be refrigerated.
“All of that makes these drugs more expensive,” says Laura Davisson, director of the weight management program at the West Virginia University Health System. “If we could get oral versions on the market, maybe the prices would come down.”
Amgen, meanwhile, thinks a less frequently taken medication could be convenient for some patients. The company is working on an injectable drug called MariTide that would be given just once a month. The drug also targets GLP-1 and GIP, but instead of stimulating GIP receptors, MariTide blocks them. It’s not entirely clear why both stimulating and blocking these receptors seems to promote weight loss.
Amgen’s approach is based on research showing that mice that lack GIP, as well as people with mutations in this receptor, have lower body weight. In results published in February, people taking MariTide in an early-stage trial lost up to more than 14 percent of their body weight in 12 weeks.
Eli Lilly is hoping to make an even more potent drug than Zepbound by adding a third mechanism involved in weight loss. It’s working on an investigational drug dubbed retatrutide that targets the receptors for GLP-1, GIP, and glucagon, the latter of which can help break down fat stores. In trial data published last year, retatrutide helped people lose more than 17 percent of their body weight, or 41 pounds, after 24 weeks. At 48 weeks, participants had lost an average of 24 percent of their body weight, or about 58 pounds—more than any other drug on the market.
“We have not seen results like this before in a trial of less than one-year duration with an anti-obesity medication,” said Ania Jastreboff, an endocrinologist and weight specialist at the Yale School of Medicine during a press conference last year at the American Diabetes Association annual meeting.