The current class of anti-obesity drugs is proving remarkably effective at removing excess kilos – but a phase three randomised clinical trial found that people who stopped taking the medication regained much of that weight within a year.
At the same time, the study, led by researchers at Weill Cornell Medicine and NewYork-Presbyterian, shows that remaining on tirzepatide not only promotes additional weight loss but preserves improvements in metabolic and cardiovascular health.
The results from the SURMOUNT-4 study, which was published in JAMA and sponsored by Eli Lilly, demonstrated that the drug can substantially help people struggling with health issues related to their weight, but it is not a quick-fix to weight loss.
“Obesity is a leading driver of many diseases that we spend our time treating in medicine; illnesses like hypertension, heart disease, diabetes and fatty liver disease are either caused by or worsened by obesity,” said lead study author Dr Louis Aronne, the Sanford I Weill Professor of Metabolic Research and director of the Comprehensive Weight Control Centre, which is part of the Division of Endocrinology, Diabetes and Metabolism at Weill Cornell Medicine.
“That we now have drugs proving to be effective is exciting and rewarding.”
Tirzepatide is part of the new class of GLP-1 receptor agonist drugs developed to treat type 2 diabetes. Besides controlling blood sugar, they also resulted in weight loss.
In a phase three randomised, controlled clinical trial last year, tirzepatide led to a 20% reduction in body weight over 72 weeks.
The US Food and Drug Administration (FDA) approved the drug last month, with the trade name Zepbound, for weight loss in individuals with a body mass index (BMI) of 30 or higher – or for those with a BMI of 27 or greater who also had health conditions like high cholesterol or hypertension.
Although the initial effects were dramatic, the researchers were uncertain whether the weight loss would persist beyond the period of active treatment.
To find out, they launched the SURMOUNT-4 trial, conducted at 70 sites in Argentina, Brazil, Taiwan and the US between March 2021 and May 2023.
The participants took a maximum tolerated dose of tirzepatide for 36 weeks, which yielded the expected weight reduction of 20.9%, with improvements in blood pressure, blood sugar metrics and lipid levels.
Then 670 eligible participants were randomly assigned to either continue with the tirzepatide for an additional year (52 weeks) or to switch to a placebo.
Those who continued on tirzepatide lost an additional 5.5% versus the placebo group, which regained 14% of their weight.
Though the placebo group was still almost 10% lighter than their initial weight, the improvements in cardiometabolic risk factors had been reversed.
Relative to placebo, tirzepatide was associated with significant improvements in BMI, lipid levels, diabetes indicators and blood pressure.
“Those who went on the placebo regained about half the weight they had lost,” said Aronne, who is also an internist specialising in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Centre.
“Whereas those who continued on the drug lost another 5%, so their overall weight loss was about 25%.”
The findings indicate that people may need to remain on tirzepatide to keep off the kilos.
“If you stop the medication, you regain the weight. There’s no question that will happen,” said Aronne.
But that shouldn’t be surprising. “Obesity is a chronic condition, like diabetes or high blood pressure. So, it must be treated chronically.”
The researchers said they didn’t evaluate the effects of intensive behavioural therapy on the maintenance of body weight reduction, which could make a difference in preventing weight regain after coming off the drug.
Mimics natural hormones
Tirzepatide works by mimicking the GLP-1 and GIP hormones that are naturally secreted by the intestine after a meal, which prompts insulin secretion.
It also reduces appetite by slowing down the time it takes the stomach to empty and interacting with areas in the brain harbouring GLP-1 receptors to signal satiety.
Since the drug mimics hormones that are produced in the gastrointestinal system, side effects tended to be nausea, vomiting, diarrhoea or constipation, and resolved with time.
The study had few people drop out because of side effects.
“People feel much better when they lose this kind of weight, so they are extremely enthusiastic about these treatments. But they also should realise this may require them to stay on the drug long term,” said Aronne.
Further studies will need to assess the long-term risks and benefits associated with these drugs, especially considering the potential for their lifelong use.
Study details
Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: The SURMOUNT-4 randomised clinical trial
Louis Aronne, Naveed Sattar, Deborah Horn, et al.
Published in JAMA Network on 11 December 2023
Key Points
Question Does once-weekly subcutaneous tirzepatide with diet and physical activity affect maintenance of body weight reduction in individuals with obesity or overweight?
Findings After 36 weeks of open-label maximum tolerated dose of tirzepatide (10 or 15 mg), adults (n = 670) with obesity or overweight (without diabetes) experienced a mean weight reduction of 20.9%. From randomisation (at week 36), those switched to placebo experienced a 14% weight regain and those continuing tirzepatide experienced an additional 5.5% weight reduction during the 52-week double-blind period.
Meaning In participants with obesity/overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.
Abstract
Importance
The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.
Objective
To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction.
Design, Setting, and Participants
This phase 3, randomised withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes.
Interventions
Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks.
Main Outcomes and Measures
The primary end point was the mean percent change in weight from week 36 (randomisation) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period.
Results
Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs 14.0% with placebo (difference, −19.4% [95% CI, −21.2% to −17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo.
Conclusions and Relevance
In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.
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