New Research Uncovers How Tirzepatide and Semaglutide Differ in Their Metabolic Effects

Recent animal studies presented at the European Congress on Obesity in Malaga, Spain, provide new insights into how tirzepatide and semaglutide, two prominent drugs for obesity treatment, uniquely influence metabolism. This research highlights that tirzepatide temporarily boosts energy expenditure, while semaglutide initially decreases it. Importantly, these metabolic changes are mostly immediate and tend to disappear quickly once treatment stops.

Both drugs are part of a class known as GLP-1 receptor agonists, which help promote weight loss primarily by reducing appetite and improving glucose control. Dr. Simone Bossi from Gubra, a Danish biotech firm, explained that weight management hinges on the balance between energy consumption and expenditure. Tirzepatide and semaglutide tip this balance toward weight loss by suppressing food intake.

The study involved feeding 24 mice a high-fat diet for 20 weeks, then dividing them into control, semaglutide, and tirzepatide groups. The mice received daily injections of the drugs for four weeks, followed by a two-week period without treatment, all while maintaining their high-fat diet. Researchers monitored energy use through indirect calorimetry, measuring oxygen consumption and carbon dioxide output, which estimate metabolic rate.

Findings showed that tirzepatide increased energy expenditure within four days, with effects peaking in the first week, without increasing physical activity levels—indicating a direct metabolic impact. After stopping the treatment, energy expenditure returned to baseline, and mice regained increased food intake.

Conversely, semaglutide caused a decrease in energy expenditure during the initial days of treatment, which normalized as the treatment continued. Both drugs resulted in greater fat oxidation, as shown by a lower respiratory exchange ratio, supporting their role in promoting fat loss. When treatment ceased, metabolic activity and fat oxidation rates increased again, coinciding with increased food intake.

Dr. Bossi pointed out that these contrasting effects on energy expenditure might partly explain why tirzepatide can lead to more significant weight loss than semaglutide. The study opens promising avenues for future therapies aimed at boosting energy expenditure for more sustainable weight management.

This research emphasizes that understanding the distinct metabolic profiles of these medications can help optimize obesity treatments and improve long-term outcomes.

Source: https://medicalxpress.com/news/2025-05-reveals-distinct-mechanisms-action-tirzepatide.html