Weight loss with tirzepatide reversed after stopping treatment

For individuals with overweight or obesity who are taking tirzepatide for weight management, continued treatment results in sustained and even augmented weight loss. When treatment is stopped, however, the achieved weight loss is substantially reversed.

In the phase III SURMOUNT-4 trial, participants received the highest tolerable weekly dose of tirzepatide subcutaneously for 36 weeks and lost 20.9 percent of their weight. Those who switched to placebo from week 36 through week 88 regained 14.0 percent of their weight, whereas those who remained on tirzepatide had further 5.5-percent weight loss (difference, −19.4 percent, 95 percent confidence interval [CI], −21.2 percent to −17.7 percent; p<0.001). [JAMA  2023;doi:10.1001/jama.2023.24945]

At week 88, most participants on tirzepatide (89.5 percent) maintained at least 80 percent of the weight loss during the lead-in period as opposed to only 16.6 percent of those on placebo (p<0.001). The overall mean weight reduction from week 0 to 88 was 25.3 percent with tirzepatide and 9.9 percent with placebo.

“A notable finding … is that after switching to placebo for 1 year, participants ended the study with substantial body weight reduction (9.9 percent). However, much of their initial improvement in cardiometabolic risk factors had been reversed,” according to the investigators.

This emphasizes the need to continue medication for successful weight management, which involves the maintenance of weight reduction and its associated cardiometabolic benefits, they added.

In terms of tirzepatide’s safety profile, the SURMOUNT-4 data were consistent with those of SURMOUNT and SURPASS trials and of studies of incretin-based therapies approved for the treatment of obesity and overweight. [N Engl J Med 2022;387:205-216; Lancet 2023;402:613-626; Lancet 2021;398:143-155; Lancet 2021;398:583-598; Lancet 2021;398:1811-1824; N Engl J Med 2021;384:989-1002]

The most common adverse events during the lead-in treatment period and the double-blind treatment period were gastrointestinal events, including nausea, diarrhoea, and vomiting.

SURMOUNT-4 included 783 participants in the lead-in treatment period and 670 participants (mean age 48 years, 71 percent women, mean weight 107.3 kg) in the double-blind treatment period.

Dual modes of action

As a dual GLP-1 agonist and GIP agonist, tirzepatide not only enhances insulin secretion but also reduces appetite by delaying stomach emptying and signalling satiety to the brain, according to principal investigator Dr Louis Aronne of Weill Cornell Medicine in New York, New York, US.

“Instead of counting calories, the medicine helps a person eat less because it signals to the brain that you’re full. The dual mechanism of action helps overcome the plateau phenomenon that is seen at some point and produces additive weight loss,” Aronne said.

“People feel much better when they lose this kind of weight, so they are extremely enthusiastic about these treatments. But they also should realize this may require them to stay on the drug long term,” he added.