Stopping Tirzepatide Led to Weight Gain, Trial Shows

After discontinuing the weight-management injectable tirzepatide (Zepbound), most patients had a hard time keeping the weight off during the phase III SURMOUNT-4 trial.

People on a maximum tolerated dose of tirzepatide (10 or 15 mg) for 36 weeks lost an average of 20.9% of their body weight. But when this group was split up and followed for another year, those who switched to placebo put back on 14% of their week 36 body weight, while those who continued on treatment lost another 5.5% (difference -19.4%, 95% CI -21.2% to -17.7%, P<0.001), Louis Aronne, MD, of Weill Cornell Medicine in New York, and colleagues reported.

At the end of the 88-week trial, the average weight loss for those on tirzepatide the whole time was 25.3% versus 9.9% for those who were switched over to placebo for a year, the group reported in JAMA.

After starting at an average body weight of 236.6 lbs (107.3 kg), tirzepatide continuers ended at a weight of 176.6 lbs (80.1 kg) versus 213.8 lbs (97 kg) for those who discontinued for a year. Around 90% of participants who took tirzepatide the entire 88 weeks maintained at least 80% of their weight loss, while only 16.6% of those who switched to placebo did the same.

“Stopping treatment will lead to weight regain as it will if treatment for any chronic metabolic disease is stopped,” Aronne told MedPage Today. “The patients regained about half the weight they had lost over the 1 year on placebo — that’s more gradual regain than I think most people would have expected.”

Aronne wasn’t particularly surprised by these findings, stating: “Obesity is a chronic disease which requires chronic treatment like diabetes, hypertension, and hyperlipidemia. If you stop treatment for those, you expect them to relapse. Same is true for obesity.”

“Evidence shows that the weight-regulating parts of the brain become resistant to the key hormones that regulate weight, that’s why it’s so hard to lose weight. These medications mimic the effect of the hormones like GLP-1 [glucagon-like peptide-1] and GIP [glucose-dependent insulinotropic polypeptide]. When you remove the effect, weight goes back to where it started, like your blood pressure, cholesterol, or blood sugar would if you stopped treatments for those,” he explained.

While it’s still unclear whether patients need to stay on these anti-obesity medications forever, Aronne said it’s to be determined whether something like a lower dose, a more intensive behavioral program, or another strategy could help with weight-loss maintenance.

The popular GLP-1/GIP receptor agonist tirzepatide was approved for chronic weight management in adults last month based on the SURMOUNT clinical program, but was approved for type 2 diabetes under the name Mounjaro in May 2022.

The first installment of the SURMOUNT series found 15 mg of the once-weekly injectable led to an average 18% increased loss of body weight compared with placebo in people with overweight (BMI≥27) or obesity (BMI ≥30) without diabetes. The second trial found people with overweight or obesity and type 2 diabetes taking the same dose lost on average 12% more of their body weight versus those randomized to placebo. Findings from SURMOUNT-3, presented at this year’s ObesityWeek meeting, found users who lost an initial 5% of weight through intensive lifestyle intervention went on to shed 20.8% of body weight over 72 weeks.

As seen in all the other installments in the clinical program, SURMOUNT-4 participants experienced gastrointestinal (GI) events most frequently (nausea 35.5%, diarrhea 21.1%, constipation 20.7%, and vomiting 16.3%), but were mostly mild to moderate. A total of 7% of tirzepatide users discontinued treatment due to adverse events, mostly GI events. Of note, dose adjustments weren’t allowed after randomization, which may not be reflective of real-world experience. Also, “those who tolerated initial treatment with 10-mg or 15-mg tirzepatide may represent a subgroup of the general population,” the researchers pointed out.

At the 36-week mark, tirzepatide was associated with significant improvements in several cardiometabolic parameters: BMI, HbA1c, fasting glucose, insulin, lipid levels, and systolic and diastolic blood pressure. But after switching to placebo for a year, most of these improvements were reversed.

All 783 participants in the trial also received lifestyle counseling by a healthcare professional and were encouraged to stick to a 500 kcal/day deficit diet and at least 150 minutes of physical activity per week. A total of 952 were screened and 783 enrolled in the 36-week lead-in period, but 113 discontinued during that period mostly due to adverse events. For enrollment, adults had to have a BMI of 30+ or 27+ with a weight-related complication, excluding diabetes.

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