Perioperative Continuation of Metformin Therapy in Patients With Typ 2 Diabetes Mellitus Undergoing Non-cardiac Surgery

Evaluation of the effect of peri-operative continuation of oral metformin therapy on the incidence of perioperative hyperglycemia compared to standard preoperative cessation of oral metformin therapy 24h before surgery.

Study Overview

• Status: Unknown
• Conditions: Hyperglycemia; Type 2 Diabetes; Hyperlactatemia; Metformin
• Intervention / Treatment: Drug: Metformin Hydrochloride

Detailed Description

Surgical procedures cause metabolic stress and can impair glucose control especially in patients with diabetes mellitus, which often results in peri-operative hyperglycemia. Peri-operative hyperglycemia is associated with impaired wound healing, secondary wound infections, endothelial dysfunction, sepsis, prolonged hospital stay and higher mortality.

Metformin is still the first line treatment in patients with type 2 diabetes mellitus.

Historically it has been stopped before surgery due to fear of hypoglycemia and metformin induced lactic acidosis. However recent studies have suggested that perioperative continuation of metformin might be safe and patients could benefit from more stable preoperative blood sugar levels.

Prospective studies evaluating the benefit of continuing oral metformin therapy in the perioperative period are rare.

The investigators plan to conduct a prospective, randomized-controlled, unblinded clinical trial where patients with type II diabetes mellitus and oral metformin therapy undergoing non-cardiac surgery will be randomized in either an interventional group or a control group. In the interventional group patients will be instructed to continue their regular metformin dose even on the day of surgery, in contrast to the control group, where the patients will be instructed to stop taking metformin 24h prior to surgery.

All other oral anti-diabetic drugs will be paused according to the local anesthesia guidelines.

The investigators plan to evaluate whether or not continuation of metformin can reduce the incidence of perioperative hyperglycemia and whether or not it is associated with elevation of blood lactate levels.

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Matthias Noitz, MD; Phone Number: +43 (0)5 7680 83 - 78171; Email: matthias.noitz@kepleruniklinikum.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 97 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-99 years
• Diabetes Mellitus Typ 2
• Oral metformin therapy
• Non cardiac-surgery
• Informed consent

Exclusion Criteria:

• Insulin therapy
• Ambulatory surgery
• Preoperative therapy with glucocorticoids (prednisolon or equivalent ≥ 5mg/day for more than 7 days)
• Planned postoperative ICU-stay
• Advanced renal insufficiency (eGFR < 45ml/kg/min)
• Advanced liver cirrhosis or failure (Child-Pugh B or C)
• Alcohol abuse
• Pregnancy,
• Perioperative administration of contrast dye

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin +; The study intervention involves the self-administration of metformin in the same dosage as the patient's regular dosage according to regular dosing schedule and randomization.	Drug: Metformin Hydrochloride; Perioperative continuation of oral metformin therapy according to the patient's normal dosage and dosage intervals; Other Names: Group A
No Intervention: Metformin -; The control group involves no intervention, which means cessation of oral metformin therapy 24 hours prior to surgery according to the local guidelines of the anesthesia department and the national anesthesiology guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Perioperative Hyperglycemia	blood glucose >180mg/dl (10mmol/l) and/or necessity of additive administration of insulin s.c. during the time frame	24 hours pre-op until 24 hours post-op

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perioperative blood glucose control	mean plasma glucose at 4 defined dates: 24h pre-op, intra-op, 2hours post-op and 24h post-op	24 hours pre-op until 24 hours post-op
Incidence hypoglycemia	blood sugar levels < 70mg/dl (3.9mmol/l)	24 hours pre-op until 24 hours post-op
Perioperative lactate levels	mediane lactate levels at 4 defined dates: 24h pre-op, intra-op, 2 hours post-op and 24h post-op	24 hours pre-op until 24 hours post-op
Incidence of hyperlactatemia	blood lactate values >4mmol/L at least at one of 4 measurement dates: 24h pre-op, intra-op, 2 hours post-op, 24 hours post-op	24 hours pre-op until 24 hours post-op
Perioperative renal function	median serum-creatinine value at 24h pre-op and 24h post-op	24 hours pre-op until 24 hours post-op
Hospitalization Duration	median time period from day of surgery until discharge from hospital	up to 4 weeks
Mortality	In-Hospital mortality	up to 4 weeks

Collaborators and Investigators

• Sponsor: Kepler University Hospital
• Investigators: Principal Investigator: Jens Meier, MD, Kepler University Hospital -Dpt. of Anesthesiology & Intensive Care Medicine

Publications and helpful links

General Publications

• Hulst AH, Polderman JAW, Ouweneel E, Pijl AJ, Hollmann MW, DeVries JH, Preckel B, Hermanides J. Peri-operative continuation of metformin does not improve glycaemic control in patients with type 2 diabetes: A randomized controlled trial. Diabetes Obes Metab. 2018 Mar;20(3):749-752. doi: 10.1111/dom.13118. Epub 2017 Oct 13.
• Gasanova I, Meng J, Minhajuddin A, Melikman E, Alexander JC, Joshi GP. Preoperative Continuation Versus Interruption of Oral Hypoglycemics in Type 2 Diabetic Patients Undergoing Ambulatory Surgery: A Randomized Controlled Trial. Anesth Analg. 2018 Oct;127(4):e54-e56. doi: 10.1213/ANE.0000000000003675.
• Kuzulugil D, Papeix G, Luu J, Kerridge RK. Recent advances in diabetes treatments and their perioperative implications. Curr Opin Anaesthesiol. 2019 Jun;32(3):398-404. doi: 10.1097/ACO.0000000000000735.
• Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010 Apr 14;2010(4):CD002967. doi: 10.1002/14651858.CD002967.pub4.

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2020
• Primary Completion (Anticipated): February 1, 2021
• Study Completion (Anticipated): April 1, 2021

Study Registration Dates

• First Submitted: February 20, 2020
• First Submitted That Met QC Criteria: February 25, 2020
• First Posted (Actual): February 26, 2020

Study Record Updates

• Last Update Posted (Actual): February 26, 2020
• Last Update Submitted That Met QC Criteria: February 25, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Diabetes Mellitus; Hyperlactatemia; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 1126/2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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