New research presented at this year's European Congress on Obesity (ECO 2026) in Istanbul, Turkey (12-15 May) and published in The Lancet shows that people who have lost weight using the maximum tolerated dose (MTD) of tirzepatide are seven times more likely to maintain that weight loss by continuing on MTD than those who stop treatment, while those who switch to a lower dose of 5 mg are four times more likely to maintain weight loss than those who stop. The study is by Dr Deborah Horn, Director of the Center for Obesity Medicine and Metabolic Performance at McGovern Medical School at UTHealth Houston, Houston, Texas, USA, and colleagues. The study was funded by Eli Lilly and Company, the manufacturer of tirzepatide.
In individuals living with obesity, initial treatment goals include bodyweight reduction and improvement in cardiometabolic risk factors. Equally important, however, is the maintenance of bodyweight reduction to sustain these benefits, which remains challenging for many patients. Weight regain after initial bodyweight reduction is common and may result from multiple factors, including premature treatment discontinuation, metabolic adaptation, and the chronic, progressive nature of the disease of obesity.
In this study, the authors evaluated the efficacy and safety of continuing tirzepatide at the maximum tolerated dose [MTD] (15 mg or 10 mg) or lowering the dose to 5 mg compared with placebo on the maintenance of body weight reduction achieved with tirzepatide MTD.
This Phase 3b, placebo-controlled, 112-week trial, including a 60-week open-label weight-loss period and a 52-week double blind weight maintenance period, was conducted across 20 sites in the United States. A total of 441 participants (aged ≥18 years, 65.3% female) with body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 and at least one weight-related complication were enrolled for the 60-week initial weight-loss period with once weekly subcutaneous tirzepatide at the MTD (10 or 15 mg). Baseline bodyweight was 113·8 kg, BMI 40·1 kg/m², and HbA1c 5·64% (38·2 mmol/mol).
To enter the weight maintenance period of the trial from week 60, participants had to lose at least 5% of bodyweight from weeks 1-60 and be able to tolerate tirzepatide 10 or 15mg. These 378 participants were then randomly assigned 3:3:2 to continue tirzepatide MTD (n=140), reduce to tirzepatide 5 mg (n=144), or switch to placebo (n=94) for the 52 weeks weight maintenance phase. The average weight of participants each group at the start of the weight maintenance phase was 88.3 kg in the tirzepatide MTD group, 88.7 kg in the tirzepatide 5 mg group, and 93.7 kg in the placebo group.
Of the 372 participants that received at least one dose of the study drug during the weight maintenance period, 33 (8.7%) participants discontinued the study drug and 33 (8.7%) discontinued the study prematurely during the weight maintenance period. A total of 345 participants (91.3%) completed the study.
Starting at week 84 (24 weeks after random allocation), participants could receive rescue tirzepatide if their weight regain exceeded 50%. Its purpose was to stop participants regaining some or all of the weight they had lost in weeks 1-60, and was received by 8% on tirzepatide MTD, 25% on tirzepatide 5 mg, and 67% on placebo.
The primary endpoint was percent change in bodyweight from baseline to Week 112. The model-based estimate percent change in bodyweight from baseline to week 112 was –21·9% with MTD, –16·6% with tirzepatide 5 mg, versus –9·9% with placebo.
All prespecified bodyweight and cardiometabolic endpoints improved during the open-label period and were sustained with continued treatment at MTD or 5 mg dose versus switch to placebo. The most common adverse events with tirzepatide were gastrointestinal events, which were mostly mild-to-moderate in severity and mostly occurred during dose escalation.
Between Week 48 and Week 60, bodyweight plateau occurred in 84%, 83%, and 85% of participants randomised to continue tirzepatide MTD, reduce to tirzepatide 5 mg, or switch to placebo, respectively (Table 1). Studying those who reached a weight plateau allowed the researchers to assess the weight maintenance phase in a weight stable population.
Among participants who reached a bodyweight plateau, those continuing tirzepatide MTD maintained 96.5% of bodyweight reduction obtained during the weight-loss period and those who reduced to the 5 mg tirzepatide dose maintained 67.9%, versus 42.8% with placebo.
Among participants who reached a bodyweight plateau, at least 80% of the bodyweight reduction achieved during the weight-loss period was maintained in 77·5% of participants treated with tirzepatide MTD, 42·4% with tirzepatide 5 mg, and 10·4% with placebo at Week 112. In other words, the odds of maintaining at least 80% of the lost bodyweight was approximately 7-times higher with continued MTD compared with placebo, and 4-times higher with reducing the dose to 5 mg compared with placebo.
Weight changes from randomisation after the 60-week initial weight loss were minimal with continuing tirzepatide MTD (–0·2 kg) – meaning on average those continuing on MTD actually lost a further 0.2kg, whereas those on tirzepatide 5 mg gained a mean of 6kg, and those switched to placebo gained a mean of 13kg.
The authors say: "Our results demonstrated that the majority of the participants continuing tirzepatide—either at MTD or reduced to 5 mg—maintained most of the bodyweight reduction initially achieved with tirzepatide MTD, though results varied with the 5-mg dose. Switching to placebo led to a substantial weight regain after the initial weight loss period despite the continued lifestyle intervention, as previously reported in tirzepatide and other obesity medication trials. Consistent with other chronic progressive diseases, the current findings show that discontinuing effective treatment in people living with obesity resulted in reversal of therapeutic benefit and caused significant weight regain, often back towards the pretreatment bodyweight over time."
They say the findings highlight the clinical importance of sustained bodyweight reduction in managing the disease of obesity and maintaining cardiometabolic health. Long-term retention of most intentional bodyweight reduction (≥75%) is associated with ongoing benefits, as shown by studies using various treatment modalities. In this trial, continued tirzepatide MTD led to preserved improvement in waist circumference, blood pressure, and lipids, while those who reduced the dose to 5 mg maintained clinically meaningful benefits to a relatively lesser extent. Conversely, tirzepatide discontinuation led to substantial weight regain and greater reversal of cardiometabolic benefits, consistent with prior studies (see table 2 full paper).
The authors highlight that the effects of tirzepatide dose adjustment (MTD, 5 mg, or placebo) on body composition — particularly muscle mass and physical function — warrant further study as key considerations in long-term obesity management. Continued tirzepatide at MTD also yielded greater quality-of-life improvements than switching to placebo. Together, these findings support sustained obesity medication for ongoing cardiometabolic and quality-of-life benefits following initial weight loss, though the degree of weight maintenance required to preserve these improvements remains to be defined.
The authors conclude: "Long-term therapy is important for maintaining bodyweight reductions and cardiometabolic benefits in adults with obesity. Compared to placebo, continued tirzepatide at the maximum tolerated dose resulted in sustained maintenance of bodyweight reduction and related health benefits, while reducing the dose to 5 mg provided superior bodyweight reduction and related health benefits compared to discontinuation, though the degree of preserving clinically meaningful benefits varied."
"Combined, these findings underscore the importance of continued therapy for long-term obesity management and provide evidence for what to expect when reducing the dosage of obesity treatment."
