Association Between Preoperative Metformin Exposure and Postoperative Nausea and Vomiting in Patients Undergoing General Anesthesia (Met-PONV)

Association Between Preoperative Metformin Exposure and Postoperative Nausea and Vomiting in Patients Undergoing General Anesthesia: a Prospective Observational Cohort Study

The aim of this observational study is to investigate the potential effects of metformin on postoperative nausea and vomiting (PONV) in patients undergoing surgery under general anesthesia. The primary research question is:

Does preoperative metformin exposure influence the incidence or severity of PONV in patients undergoing general anesthesia? Patients who are already prescribed metformin as part of their routine medical management will be compared with those not taking metformin. Data on PONV occurrence, severity, and recovery outcomes will be collected through structured postoperative surveys administered after surgery.

Study Overview

• Status: Recruiting
• Conditions: Postoperative Nausea and Vomiting

Detailed Description

This is a prospective observational cohort study involving patients undergoing surgery under general anesthesia with endotracheal intubation at the Sixth Affiliated Hospital of Sun Yat-sen University. A total of 909 participants will be enrolled into either the metformin-exposed group (n=303) or the non-exposed group (n=606) . The primary outcome is the incidence of postoperative nausea and vomiting (PONV) within 0-120 hours after surgery. Secondary outcomes comprise the incidence and severity of PONV during different intervals, use of antiemetics, and quality of recovery (assessed by the QoR-15 score).

• Study Type: Observational
• Enrollment (Estimated): 909

Contacts and Locations

• Study Contact: Name: Yang Zhao, Doctor; Phone Number: 0086-02038254070; Email: zhaoy47@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510655
      • Recruiting
      • The Sixth Affiliated Hospital, Sun Yat-sen University
      • Contact: Yang Zhao, Doctor; Phone Number: 0086-13802435520; Email: zhaoy47@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients scheduled for surgery under general anesthesia with tracheal intubation

Description

Inclusion criteria

1. Voluntarily sign the informed consent form;
2. Age ≥ 18 years;
3. Patients who require surgical treatment under endotracheal intubation with general anesthesia as determined by the treating physician.

Exclusion criteria

1. Emergency surgery;
2. Currently taking medications with established antiemetic effects (e.g., corticosteroids, antipsychotics) due to underlying medical conditions;
3. Cognitive impairment or psychiatric disorders that preclude cooperation with questionnaire assessments;
4. Anticipated inability to extubate the tracheal tube postoperatively, which would interfere with outcome assessment;
5. Presence of nausea and/or vomiting prior to surgery.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Exposure group; Patients are already prescribed metformin before surgery
The non-exposure group; Patients are not prescribed metformin before surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of PONV during 0-120 postoperative hours	PONV is defined as the occurrence of any of the following symptoms: nausea, retching, or vomiting	During 0-120 hour after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence PONV during 0-24 hour after surgery	PONV is defined as the occurrence of any of the following symptoms: nausea, retching, or vomiting	During 0-24 hour after surgery
The incidence PONV during 24-120 hour after surgery	Trained blinded investigators collected information about PONV recorded by either the participants and their family members or medical staff in the ward every 24 h during the first 120 h after surgery.	During 24-120 hour after surgery
The total severity of PONV during 0-120 hour after surgery	Assessment was performed using a simplified Postoperative Nausea and Vomiting (PONV) Impact Scale. Nausea severity was scored as follows: 0 (none), 1 (occasional), 2 (frequent), and 3 (continuous). Vomiting or retching was scored based on the number of episodes: 0, 1, 2, or 3 (or ≥3 episodes). The scores for nausea and vomiting/retching were summed to generate a total daily score for each 24-hour postoperative period. A total daily score of ≥5 was defined as clinically significant PONV. The overall PONV severity from 0 to 120 hours postoperatively was calculated as the sum of the daily scores over this period, providing a cumulative measure of symptom burden.	During 0-120 hour after surgery
The severity of PONV during 0-24 hour after surgery	Assessment was performed using a simplified Postoperative Nausea and Vomiting (PONV) Impact Scale. Nausea severity was scored as follows: 0 (none), 1 (occasional), 2 (frequent), and 3 (continuous). Vomiting or retching was scored based on the number of episodes: 0, 1, 2, or 3 (or ≥3 episodes). The scores for nausea and vomiting/retching were summed to generate a total daily score for each 24-hour postoperative period. A total daily score of ≥5 was defined as clinically significant PONV.	During 0-24 hour after surgery
The severity of PONV during 24-120 hour after surgery	Assessment was performed using a simplified Postoperative Nausea and Vomiting (PONV) Impact Scale. Nausea severity was scored as follows: 0 (none), 1 (occasional), 2 (frequent), and 3 (continuous). Vomiting or retching was scored based on the number of episodes: 0, 1, 2, or 3 (or ≥3 episodes). The scores for nausea and vomiting/retching were summed to generate a total daily score for each 24-hour postoperative period. A total daily score of ≥5 was defined as clinically significant PONV. The overall PONV severity from 25 to 120 hours postoperatively was calculated as the sum of the daily scores over this period.	During 24-120 hour after surgery
Use of antiemetics during 0-24 hours after surgery	Use of antiemetics after surgery	During 0-24 hours after surgery
Use of antiemetics during 24-120 hours after surgery	Use of antiemetics after surgery	During 24-120 hours after surgery
Use of antiemetics during 0-120 hours after surgery	Use of antiemetics after surgery	During 0-120 hours after surgery
Quality of Recovery (QoR-15 score) from 0 to 120 hour after surgery	The QoR-15 is a 15-item questionnaire instrument designed to evaluate the quality of postoperative recovery in patients. It comprises five sub-scales: pain (2 items), physical comfort (5 items), physical independence (2 items), psychological support (2 items), and emotional state (4 items). Each item is scored from 0 to 10, resulting in a total score ranging from 0 to 150. A higher score indicates a better quality of recovery for the patient.	Evaluated before surgery, at 24-hour, 48-hour, 72-hour, 96-hour, 120-hour after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival rates	The status of live or death, and the death time	1-year, 3-year, 5-year after surgery
Disease-free survival rates at 1-year, 3-year and 5-year, assessed exclusively among patients with cancer.	Disease-free survival rates	1-year, 3-year and 5-year after surgery
Quality of recovery at 30-day after surgery	The QoR-15 is a 15-item questionnaire instrument designed to evaluate the quality of postoperative recovery in patients. It comprises five sub-scales: pain (2 items), physical comfort (5 items), physical independence (2 items), psychological support (2 items), and emotional state (4 items). Each item is scored from 0 to 10, resulting in a total score ranging from 0 to 150. A higher score indicates a better quality of recovery for the patient.	At 30-day after surgery
Incidence and grade of major postoperative complications	Incidence and grade of major postoperative complications	During 30 day after surgery
PONV-related factors in the blood or urine.	PONV-related factors in the blood or urine	from preoperative to postoperative

Collaborators and Investigators

• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University
• Investigators: Principal Investigator: Yang Zhao, Dr, The Sixth Affiliated Hospital, Sun Yat-sen University

Publications and helpful links

General Publications

• Myles PS, Wengritzky R. Simplified postoperative nausea and vomiting impact scale for audit and post-discharge review. Br J Anaesth. 2012 Mar;108(3):423-9. doi: 10.1093/bja/aer505. Epub 2012 Jan 29.
• Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology. 1999 Sep;91(3):693-700. doi: 10.1097/00000542-199909000-00022.
• Bu XS, Zhang J, Zuo YX. Validation of the Chinese Version of the Quality of Recovery-15 Score and Its Comparison with the Post-Operative Quality Recovery Scale. Patient. 2016 Jun;9(3):251-9. doi: 10.1007/s40271-015-0148-6.
• Sillis L, Heinonen EW, Ceulemans M, Johnson D, Luo Y, Chambers CD. Metformin for the Prevention of Hyperemesis Gravidarum: An Observational Cohort Study. BJOG. 2025 Nov;132(12):1772-1778. doi: 10.1111/1471-0528.18238. Epub 2025 May 29.
• Day EA, Ford RJ, Smith BK, Mohammadi-Shemirani P, Morrow MR, Gutgesell RM, Lu R, Raphenya AR, Kabiri M, McArthur AG, McInnes N, Hess S, Pare G, Gerstein HC, Steinberg GR. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat Metab. 2019 Dec;1(12):1202-1208. doi: 10.1038/s42255-019-0146-4. Epub 2019 Dec 9.
• Mai Y, Zhang S, Huang Q, Liang C, Shi J, Zheng J, Lv K, Liu H, Yang X, Zhao Y. Association between plasma growth differentiation factor-15 and postoperative nausea and vomiting incidence and severity: a secondary analysis of a randomised trial. Br J Anaesth. 2025 Aug;135(2):459-468. doi: 10.1016/j.bja.2025.05.001. Epub 2025 May 29.
• Hsu JY, Crawley S, Chen M, Ayupova DA, Lindhout DA, Higbee J, Kutach A, Joo W, Gao Z, Fu D, To C, Mondal K, Li B, Kekatpure A, Wang M, Laird T, Horner G, Chan J, McEntee M, Lopez M, Lakshminarasimhan D, White A, Wang SP, Yao J, Yie J, Matern H, Solloway M, Haldankar R, Parsons T, Tang J, Shen WD, Alice Chen Y, Tian H, Allan BB. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature. 2017 Oct 12;550(7675):255-259. doi: 10.1038/nature24042. Epub 2017 Sep 27.
• Cheng W, Gordian D, Ludwig MQ, Pers TH, Seeley RJ, Myers MG Jr. Hindbrain circuits in the control of eating behaviour and energy balance. Nat Metab. 2022 Jul;4(7):826-835. doi: 10.1038/s42255-022-00606-9. Epub 2022 Jul 25.
• Borner T, Tinsley IC, Milliken BT, Doebley SA, Najjar NR, Kerwood DJ, De Jonghe BC, Hayes MR, Doyle RP. Creation of a Peptide Antagonist of the GFRAL-RET Receptor Complex for the Treatment of GDF15-Induced Malaise. J Med Chem. 2023 Aug 24;66(16):11237-11249. doi: 10.1021/acs.jmedchem.3c00667. Epub 2023 Jul 28.
• Liu ZY, Yang XY, Lv C, Ye L, Chen JJ, Chen XY, Wang SP, Wu L, Zhang WQ, Lu M, Guo XW. Effect of High Maintenance Dose Versus Low Dose of Remifentanil on Incidence of Postoperative Nausea and Vomiting (PONV) in Patients Under Gynecological Laparoscopic Procedure: A Pilot Study. Drug Des Devel Ther. 2025 Jun 7;19:4885-4894. doi: 10.2147/DDDT.S518291. eCollection 2025.
• Zhang Q, Ye X, Shi S, Zhou S, Ma D, Ouyang W, Tong J, Le Y. Pyridoxine Prevents Postoperative Nausea and Vomiting in Gynecologic Laparoscopic Surgery: A Double-blind Randomized Controlled Trial. Anesthesiology. 2025 Apr 1;142(4):655-665. doi: 10.1097/ALN.0000000000005354. Epub 2024 Dec 27.
• Sharma N, MacGibbon KW, Brecht-Doscher A, Cortessis VK, Fejzo MS. Prepregnancy metformin use associated with lower risk of severe nausea and vomiting of pregnancy and hyperemesis gravidarum. Am J Obstet Gynecol. 2025 Dec;233(6):649.e1-649.e14. doi: 10.1016/j.ajog.2025.06.055. Epub 2025 Jun 28.
• Kincaid JWR, Rimmington D, Tadross JA, Cimino I, Zvetkova I, Kaser A, Richards P, Patel S, O'Rahilly S, Coll AP. The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15. Sci Rep. 2024 Jan 22;14(1):1899. doi: 10.1038/s41598-024-51866-2.
• Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11514-9. doi: 10.1073/pnas.94.21.11514.
• Al-Kuraishy HM, Al-Gareeb AI, Alexiou A, Papadakis M, Nadwa EH, Albogami SM, Alorabi M, Saad HM, Batiha GE. Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure. J Diabetes. 2022 Dec;14(12):806-814. doi: 10.1111/1753-0407.13334. Epub 2022 Nov 28.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2033

Study Registration Dates

• First Submitted: November 17, 2025
• First Submitted That Met QC Criteria: November 17, 2025
• First Posted (Actual): November 24, 2025

Study Record Updates

• Last Update Posted (Actual): February 9, 2026
• Last Update Submitted That Met QC Criteria: February 5, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Postoperative Complications; Pathologic Processes; Signs and Symptoms, Digestive; Vomiting; Nausea; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Postoperative Nausea and Vomiting
• Other Study ID Numbers: E2025278

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: only IPD used in the results publication
• IPD Sharing Time Frame: The data will become available after the manuscript is published.
• IPD Sharing Access Criteria: The request for the analytic code shall be sent to Prof. Yang Zhao, Email-address: zhaoy47@mail.sysu.edu.cn
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No