Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss

BACKGROUND: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain. METHODS: In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance. RESULTS: Soluble leptin receptor increase was 59% lower; 2.1±0.7 vs 5.1±0.8 ng ml(−1) (−3.0 (95% confidence interval (CI)=−0.5 to −5.5)), P<0.001 and free leptin index decrease was 43% smaller; −62±15 vs −109±20 (−47 (95% CI=−11 to −83)), P<0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (−2.3 kg (95% CI=−0.6 to −4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=−0.6 to −1)), P<0.001. Fasting glucose was decreased by an additional −0.2±0.1 mmol l(−1) in the GLP-1RA group in contrast to the control group, where glucose increased 0.3±0.1 mmol l(−1) to the level before weight loss (−0.5mmol l(−1) (95% CI=−0.1 to −0.9)), P<0.005. Meal response of peptide PYY(3–36) was higher at week 52 in the GLP-1RA group compared with the control group, P<0.05. CONCLUSIONS: The weight maintaining effect of GLP-1RAs may be mediated by smaller decrease in free leptin and higher PYY(3–36) response. Low dose GLP-1RA therapy maintained 12% weight loss for 1 year and may prevent pre-diabetes in obesity.