Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation.

Summary

In calorie-restricted obese mice, tirzepatide attenuated metabolic adaptation and increased fat oxidation. In a phase 1 trial in people with obesity, tirzepatide increased fat oxidation and reduced appetite and ad libitum energy intake versus placebo, but did not measurably attenuate metabolic adaptation, clarifying mechanism-of-action across species.

Key Findings

• In obese mice, tirzepatide attenuated the drop in energy expenditure seen with calorie restriction and lowered respiratory exchange ratio, indicating increased fat oxidation.
• In humans with obesity (phase 1), tirzepatide increased fat oxidation and reduced appetite and ad libitum caloric intake compared with placebo.
• No measurable attenuation of metabolic adaptation was detected in humans despite increased fat oxidation, highlighting species differences and mechanistic nuance.

Clinical Implications

Clinicians can emphasize substrate utilization shifts and appetite suppression rather than reduced metabolic adaptation when counseling on tirzepatide; pairing with lifestyle strategies targeting energy expenditure may optimize outcomes.

Limitations

• Phase 1 human study with small sample size and short, acute metabolic assessments.
• Energy expenditure findings differ between species; long-term clinical relevance requires further trials.

Future Directions

Test long-term effects on energy expenditure and substrate utilization in larger randomized trials, and evaluate combination strategies (e.g., exercise) to counter metabolic adaptation.