Dr Deborah Horn
The first randomised trial to test “step-down” obesity pharmacotherapy suggests some patients may be able to reduce tirzepatide to a lower maintenance dose after major weight loss while preserving much of the benefit lost when treatment is stopped altogether.
Results from the phase 3b SURMOUNT-MAINTAIN trial, published in The Lancet [link here], showed patients who stepped down to tirzepatide 5 mg weekly regained substantially less weight over the following year than those switched to placebo, while ongoing maximum-dose therapy delivered the strongest maintenance of weight loss and cardiometabolic improvement.
Investigators said the findings provide the first evidence for a potential middle ground between lifelong maximal dosing and complete treatment cessation – a question becoming increasingly important as clinicians and patients grapple with the long-term affordability of obesity pharmacotherapy.
In the US-based trial, Dr Deborah Horn, obesity medicine specialist and Clinical Professor at the University of Texas McGovern Medical School, and colleagues enrolled 441 adults with obesity into a 60-week open-label lead-in phase using tirzepatide escalated to the maximum tolerated dose of either 10 mg or 15 mg weekly.
By randomisation, participants had reduced mean BMI from 40.1 kg/m² to approximately 31 kg/m², with many losing more than 20% of their body weight. Participants were then assigned to continue maximum-dose tirzepatide, reduce to 5 mg weekly, or switch to placebo for a further 52 weeks.
After 112 weeks of total follow-up, ongoing maximum-dose tirzepatide maintained the greatest weight reduction.
Key efficacy findings included:
Mean weight change from baseline:
- 21.9% with maximum-dose tirzepatide
- 16.6% with tirzepatide 5 mg
- 9.9% with placebo
Weight change after randomisation:
- Weight remained essentially stable with maximum-dose tirzepatide
- Approximately 7% weight regain with tirzepatide 5 mg
- 15.2% weight regain with placebo
Rescue tirzepatide requirement for patients regaining at least 50% of lost weight:
- 8% with maximum-dose tirzepatide
- 25% with tirzepatide 5 mg
- 67% with placebo
Gastrointestinal adverse events, including nausea, diarrhoea and vomiting, remained the most common side effects during the maintenance phase. Most were mild to moderate and generally improved over time. No new safety signals emerged.
In a linked editorial [link here], Professor André Scheen, endocrinologist at the University of Liège, Belgium, and Professor Jean-Michel Oppert, Professor of Nutrition at Sorbonne University and Pitié-Salpêtrière Hospital in Paris, described the study as “the first obesity trial to investigate the effect of reducing the dose of an effective obesity medication” on maintenance of weight reduction.
They said the findings strengthened the rationale for maintaining obesity pharmacotherapy at the “lowest effective dose”, but argued the study left the question of which patients are most likely to succeed on lower-dose maintenance therapy unresolved.
Identifying suitable candidates for dose reduction would be “crucial information” for more personalised obesity care, they wrote.
Importantly, they also noted that restrictions on intensive behavioural therapy during the maintenance phase may have amplified weight regain after treatment withdrawal. Indirect comparisons, they wrote, suggest patients may regain weight more rapidly after stopping obesity medications than after structured behavioural interventions alone.
Dr Paige Lanyon-Roberts
Speaking with the limbic, Queensland bariatric GP Dr Paige Lanyon-Roberts, who was not involved in the study, said the findings were likely to prove most useful in helping clinicians frame long-term treatment discussions with patients.
“Where I think this trial is going to be important in the doctor’s office is in being able to talk to patients about the need for ongoing therapy,” she said.
“Obesity is a chronic disease. We want to treat this condition lifelong, but we know there are barriers, particularly financial barriers, to patients being able to stay on the medications for that period of time.”
The findings add to growing evidence that incretin-based therapies suppress – rather than permanently reverse – the biological mechanisms that drive weight regain after weight loss.
“The problem was never the person,” Dr Lanyon-Roberts said.
“It was never their willpower or their ability to stick to a diet. The problem is the pathology, and this disease requires long-term treatment.”
She said the lower-dose maintenance findings may offer clinicians and patients a more realistic long-term strategy than complete discontinuation.
“You can almost guarantee you’re regaining the weight if you go back to nothing,” she said.
“But if we reduce the dose, it will be more cost-effective for you, and what you get to do is maintain those cardiometabolic benefits that you didn’t have before you lost the weight.”
Those benefits were largely preserved among patients who remained on tirzepatide.
Compared with placebo, participants maintained on tirzepatide demonstrated:
- Greater reductions in systolic blood pressure
- Sustained improvements in:
• HbA1c
• Triglycerides
• Waist circumference
• Higher rates of normoglycaemia among participants with prediabetes at baseline:
• 92.7% with maximum-dose tirzepatide
• 84.4% with tirzepatide 5 mg
• 51.0% with placebo
The editorialists said the findings reinforced a growing clinical reality that obesity management may increasingly resemble other chronic disease models requiring long-term pharmacotherapy. However, they cautioned that 52 weeks remained a relatively short maintenance period for a chronic disease such as obesity and called for longer-term follow-up, cost-effectiveness analyses and studies examining how lifestyle interventions and resistance exercise might optimise long-term outcomes.
For Australian clinicians, the findings are also likely to sharpen ongoing questions around affordability and access. While six obesity medications are approved by the Therapeutic Goods Administration, none are currently listed on the Pharmaceutical Benefits Scheme specifically for weight loss.
The study was funded by Eli Lilly.