301-OR: Synergistic Effects of Dapagliflozin and Tirzepatide Combination Treatment on Weight Loss and Glucose Regulation in Diet-Induced Obese Animals

Background: Tirzepatide is a dual GLP-1 and GIP receptor agonist that enhances glucose-stimulated insulin secretion and significantly lowers HbA1c as well as weight. SGLT2 has also been shown to reduce weight in addition to their glucose lowering effect. Given their different modes of action we hypothesized that their combination would produce additive improvements in weight loss as well as their glycemic control.

Methods: A total of 40 male Sprague Dawley rats aged 6-8 weeks were fed a Normal Diet or high-fat cafeteria diet for 12 weeks. Animals on high fat diet were then divided into four groups treated with either placebo, 100 nmole/kg Tirzepatide, Dapagliflozin 1mg/kg or a combination of Dapagliflozin and Tirzepatide for 6 weeks. Weight, FBG, and calorie consumption were monitored on a weekly basis. The study concluded with the administration of OGTT and ITT tests, followed by the collection of various tissues.

Results: After treatment, animals on normal diet weight of 522.9±11.7g, placebo-treated obese animals were 671.3 ± 26.2g, compared to 598.9 ± 23.4g in dapagliflozin-treated, 532.3±23.0g in Tirzepatide-treated animals, and 480.7± 18.8 g in animals treated with the combination (p<0.001). The addition of dapagliflozin to Tirzepatide resulted in a significant additive improvement in glucose AUC compared to Tirzepatide alone. Moreover, omental, and subcutaneous adipose tissue weight was significantly decreased in animals treated with the combination compared to Tirzepatide alone.

Conclusion: The addition of dapagliflozin to tirzepatide resulted in further weight reduction and improvement in glycemic control compared to each drug alone.