Is Sustained Calorie Reduction the Key to Semaglutide’s Long-Term Weight Loss? New Trial Suggests Yes

Semaglutide 2.4 mg maintained significantly lower energy intake over 60 weeks in adults with overweight or obesity, according to a double-blind randomized controlled trial published in The American Journal of Clinical Nutrition. Although the drug’s appetite-suppressing effects diminished over time, participants continued to consume substantially fewer calories than those receiving placebo, suggesting that mechanisms beyond subjective appetite suppression contribute to its long-term weight-loss effects.

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist approved for chronic weight management, has previously been shown to reduce appetite, energy intake and food reward during short-term treatment. However, whether these effects persist during long-term therapy remained uncertain. The present study evaluated whether semaglutide continues to influence eating behaviour after weight loss begins to plateau.

Trial assessed eating behaviour over 60 weeks

The 60-week, single-centre, double-blind trial (NCT05548647) enrolled 120 adults with overweight or obesity, who were randomized in a 3:2 ratio to receive once-weekly semaglutide 2.4 mg (72 participants) or placebo (48 participants). All participants also received standardized lifestyle counselling. Laboratory assessments at baseline and weeks 20, 40 and 60 measured objective energy intake, subjective appetite and food reward.

Participants consumed approximately 240 to 292 fewer calories than placebo

The primary endpoint showed that semaglutide consistently reduced calorie intake throughout treatment. Compared with placebo, participants receiving semaglutide consumed 291.9 fewer kcal at week 20, 240.2 fewer kcal at week 40 and 269.5 fewer kcal at week 60 during standardized laboratory meals. Overall energy intake remained approximately 30% lower at week 20, 25% lower at week 40 and 22% lower at week 60 versus placebo, demonstrating sustained reductions even after weight loss had slowed or plateaued.

Appetite effects declined, but lower food intake persisted

Semaglutide produced significantly greater appetite suppression and reductions in hunger and food preoccupation during the first 20 weeks of treatment. However, by weeks 40 and 60, differences in subjective appetite between treatment groups were no longer statistically significant. Despite this, participants receiving semaglutide continued to consume substantially fewer calories than those receiving placebo, indicating that sustained reductions in energy intake are not explained by appetite suppression alone.

Semaglutide also significantly reduced responsiveness to the rewarding value of food at weeks 20 and 40, although this difference was no longer statistically significant by week 60. The investigators suggested that continued changes in food reward may help support lower calorie intake during long-term treatment.

Weight loss reached approximately 15% at one year

Although weight loss was not the primary endpoint, participants receiving semaglutide lost an average of 15.4 kg (15.1% of baseline body weight) by week 60 compared with 3.6 kg (3.4%) in the placebo group. The investigators concluded that sustained reductions in energy intake are a key mechanism through which semaglutide both induces initial weight loss and helps maintain it over time.

Safety profile remained consistent with previous studies

The safety findings were consistent with the established profile of semaglutide 2.4 mg. Gastrointestinal adverse events, including nausea, constipation, vomiting and diarrhoea, were the most frequently reported events. Three serious adverse events occurred in the semaglutide group, including appendicitis, cholelithiasis and acute bronchitis, while no serious adverse events occurred in the placebo group. No deaths or new safety signals were reported.

Clinical implications

The authors noted that patients may perceive semaglutide as becoming less effective because subjective appetite suppression gradually diminishes during long-term treatment. However, the objective reduction in calorie intake persists despite these changing perceptions, suggesting that continued therapy supports weight maintenance through behavioural mechanisms extending beyond appetite suppression alone.

The investigators concluded that semaglutide 2.4 mg continues to help individuals consume significantly fewer calories over prolonged treatment despite attenuation of some subjective appetite benefits. The findings strengthen the evidence that sustained reductions in energy intake are central to the drug’s long-term weight-management effects.

Reference

Short- and long-term effects of semaglutide 2.4 mg on energy intake, appetite, and food reward: a 60-week, double-blind randomized controlled trial – ScienceDirect