AbstractHenagliflozin proline and metformin hydrochloride sustained‐release tablets (HR20033) are a fixed‐dose combination of the novel, highly selective, and effective sodium‐glucose cotransporter‐2 inhibitor henagliflozin, with a metformin sustained‐release layer for the treatment of type 2 diabetes mellitus in conjunction with dietary control and exercise. The aims of this study were to investigate the effect of a high‐fat diet on the pharmacokinetics of henagliflozin and metformin after a single administration of HR20033 and the effect of repeated oral administration of HR20033 on their pharmacokinetics in healthy volunteers. The food‐effect clinical study involved 18 healthy subjects randomized to receive either HR20033 in the fasted condition followed by HR20033 in the fed condition or the reverse schedule, with the two doses separated by a washout period of at least 7 days. The multiple‐dose clinical study was conducted on 10 healthy subjects. In the food‐effect study, compared with those in the fasted condition, the area under the blood concentration curve (AUC) and peak concentration (Cmax) of henagliflozin decreased by 12.64% and 40.89%, respectively, while the AUC of metformin increased by 31.13% and Cmax decreased by 7.09% in the fed state. There was no significant accumulation of HR20033 in the body after multiple oral doses. No serious adverse event was observed in either of the two clinical studies. Food did not have a clinically meaningful effect on the absorption of HR20033.