Tirzepatide Serves Up Major Weight-Loss Win in Patients With Obesity

The combination GIP and GLP-1 receptor agonist tirzepatide (Mounjaro) could soon be the next new treatment option for people with overweight or obesity, researchers reported.

In the 72-week, phase III SURMOUNT-1 clinical trial, people with obesity, but without diabetes, on 15 mg of the once-weekly injectable had a mean percentage change in weight of -20.9% (95% CI -21.8 to -19.9%) versus -3.1% (95% CI -4.3 to -1.9) with placebo, according to Ania M. Jastreboff, MD, PhD, of the Yale University School of Medicine in New Haven, and colleagues.

People on the two lower doses also saw significant average drops in body weight by the end of the trial compared with placebo:

• 5 mg: -15.0% (95% CI -15.9 to -14.2)
• 10 mg: -19.5% (95% CI -20.4 to -18.5)

A total of 85%, 89%, and 91% of patients on the 5-mg, 10-mg, and 15-mg doses achieved a clinically meaningful weight reduction of 5% or more versus only 35% of placebo who achieved the same. Additionally, 50% and 57% of adults in the two higher doses achieved a 20% or greater weight loss versus only 3% of placebo.

Developer Eli Lilly announced topline data from the trial earlier last month. Full results were presented at the American Diabetes Association (ADA) annual meeting and simultaneously published in the New England Journal of Medicine.

"This is a new era for obesity treatment," Jastreboff stated during an ADA press conference. "There were first-generation medicines, second-generation medicines, which were about 2010 to 2020. Starting last year with semaglutide [Wegovy] and now tirzepatide, this is a new era for obesity treatment."

"Those medications are much more highly effective than any other medications we've had for the treatment of obesity right now. They are clearly exceeding the greater than or equal to 5% weight reduction target," she pointed out. "What we really need to focus on is [that] this is a new era for our patients; this is a new era for physicians caring for patients with obesity -- which is all of us -- and we now have the tools, and will have more tools going forward, to be able to treat our patients with obesity."

For the efficacy estimand, the average drop in body weight for the 5-mg, 10-mg, and 15-mg doses were 16.1 kg (35.5 lb), 22.2 kg (48.9 lb), and 23.6 kg (52.0 lb), respectively. In the subgroup of patients who underwent dual-energy x-ray absorptiometry (DXA) scans, there was a 25.7% greater reduction in total body fat mass versus placebo.

Beyond just weight loss, tirzepatide treatment resulted in improvements in waist circumference, systolic and diastolic blood pressure, fasting insulin level, and lipid levels. SF-36 physical function scores also increased more with active treatment, according to the authors.

As to be expected with a GLP-1 receptor agonist, the most common adverse events (AEs) were gastrointestinal-related: nausea, diarrhea, and constipation. There were four cases of adjudication-confirmed pancreatitis, one in each of the study arms including placebo.

Most of the GI AEs occurred during the dose-escalation phase and then decreased over time, Jastreboff said. She stated that clinicians need to work with their patients to manage these AEs, seeing if down-titration is needed or if patients are eating past the point of fullness, spurring these AEs.

"Welcome to GLP-1 receptor agonists," commented Robert Eckel, MD, of the University of Colorado, during the press conference.

The first of its kind in this class of combination GLP-1/GIP drugs, tirzepatide was FDA approved in May for type 2 diabetes, based on findings of the SURPASS clinical program.

The agent is set up to follow in the footsteps of other GLP-1 receptor agonists that have since earned weight management indications on top of diabetes indications. Some of these options include 30-mg liraglutide (Saxenda) and the blockbuster 2.4-mg semaglutide, both approved as adjunct to lifestyle modification.

"The type of comparator trial that's really needed is a randomized controlled trial with semaglutide or tirzepatide versus metabolic surgery," said Eckel, who wasn't involved with the current study. "That's very desperately needed now to [help] patients make the best choices for themselves individually."

The trial had 2,539 adults with overweight or obesity (baseline mean BMI 38) without diabetes, although 40% had prediabetes. The total study population age was about 45, and they were mostly female and white.

Jastreboff highlighted the difference in weight loss seen between this trial versus the SURPASS clinical program that assessed tirzepatide in people with diabetes. In the latter, patients on 15 mg of tirzepatide saw an average drop of 8.8 kg (19.4 lb).

"The weight reduction in people with diabetes is lower than in people who don't yet have diabetes," she explained. "There is something different about patients once they've already developed type 2 diabetes where they lose less weight with these agents."

"I think this is incredibly key because what message does that send," she said. "It sends the message that we are treating patients too late. We should be treating patients when they have obesity before they develop type 2 diabetes. We can help their health more."

"I think we should be treating patients earlier," she emphasized.

Jastreboff added that SURMOUNT-1 will continue for another 2 years for the 40% of participants that had prediabetes in order to see if they had different weight reductions than those without prediabetes at baseline.

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