Oral Peri-operative TIming of Metformin (or) Salsalate to Improve Non-cardiac Surgery Glucose Control

NCT03816488 | Withdrawn Phase 1

• 1 other identifier: 5451
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Hypothesis: In surgical patients with type 2 diabetes, taking either metformin or salsalate on the morning of surgery will reduce the incidence of hyperglycemia, inflammation and even surgical site infections, without any obvious patient risk relative to patients given a placebo control. Anesthesia and surgery induce a number of metabolic disturbances, particularly among patients with type 2 diabetes (T2D). This includes altered glucose metabolism and hyperglycemia, which is associated with significant morbidity and mortality, including an increase in surgical site infections (SSI). Although insulin protocols can reduce blood glucose levels in hyperglycemic surgical patients, leading to reduced SSI, this has caused severe hypoglycemia in a number of patients. Instead, the use of simple and effective interventions, such as continuing metformin on the day of surgery, could represent an important step toward reducing the incidence of these morbid outcomes while improving glucose control. Alternatively, salsalate, a non-acetylated dimer of salicylic acid, has also emerged as a novel glucose-lowering medication that also possesses important anti-pyretic and anti-inflammatory properties and could prove equally effective.These refinements may also reduce SSI and inflammation. If the proposed pilot trial, to continue metformin, or take salsalate, peri-operatively, is as safe and easy as the investigators anticipate it will allow for the planning of a future definitive randomized clinical trial. The aims of this pilot trial are to assess the feasibility of safely continuing metformin, or taking salsalate on the day of surgery, with the goal of reducing the incidence of hyperglycemic events. This includes assessing our ability to recruit patients, adhere to the proposed study protocol, assess workload,and measure the desired outcomes, all of which are crucial for the planning of a subsequent clinical trial.

Conditions

Diabetes Mellitus, Type 2; Hyperglycemia; Perioperative/Postoperative Complications

Keywords

Metformin; Salsalate

Outcome Measures

Primary Outcomes (3)

• Feasibility: recruitment rate (percentage)

  Percentage (%) of individuals who were approached in the pre-operative clinic that enrolled in the study

  One year

• Participants with hyperglycemia

  Detect change in hyperglycemic events (glucose \>11mmol/L) at the 4 blood sampling time points for each participant

  One year

• Feasibility: recruitment rate (total number per month)

  Number (n) of individuals recruited each month

  One year

Secondary Outcomes (2)

• Blood glucose levels (glycemic control)

  One year

• Number of participants with inflammation

  One year

Study Arms (3)

Metformin

EXPERIMENTAL

Self-administered metformin (patient's usual dose) taken 2 hours prior to surgery

Drug: Metformin

Salsalate

EXPERIMENTAL

Self-administered salsalate taken 2 hours prior to surgery

Drug: Salsalate

Placebo

NO INTERVENTION

Self-administered placebo taken 2 hours prior to surgery

Interventions

Metformin DRUG

Metformin (usual dose) administered 2 h before surgery

Metformin

Salsalate DRUG

Salsalate 1.5 g administered 2 h before surgery

Salsalate

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Elective surgical patients requiring a general anesthetic at HHS requiring at least an overnight admission;
• Using metformin regularly for control of T2D;
• American Society of Anesthesiologists (ASA) physical classification I, II and III;
• Less than 1000 mL of blood loss is expected.

You may not qualify if:

• Procedures for which non-steroidal anti-inflammatory drugs are contraindicated;
• Diagnosis of renal failure (estimated glomerular filtration rate \<60 mL/min/1.73m2);
• Liver failure;
• Previous episodes of congestive heart failure;
• Severe hypoglycemia in the past year;
• Conditions masking hypoglycemia (e.g. autonomic neuropathy);
• Low random blood glucose during pre-screening (≤4.0 mmol/L);
• Received contrast within 48h prior to, or during, surgery.

Sponsors & Collaborators

• McMaster University: lead

Related Publications (4)

• Palermo NE, Gianchandani RY, McDonnell ME, Alexanian SM. Stress Hyperglycemia During Surgery and Anesthesia: Pathogenesis and Clinical Implications. Curr Diab Rep. 2016 Mar;16(3):33. doi: 10.1007/s11892-016-0721-y.

  PMID: 26957107 BACKGROUND

• Frisch A, Chandra P, Smiley D, Peng L, Rizzo M, Gatcliffe C, Hudson M, Mendoza J, Johnson R, Lin E, Umpierrez GE. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care. 2010 Aug;33(8):1783-8. doi: 10.2337/dc10-0304. Epub 2010 Apr 30.

  PMID: 20435798 BACKGROUND

• Membership of the Working Party; Barker P, Creasey PE, Dhatariya K, Levy N, Lipp A, Nathanson MH, Penfold N, Watson B, Woodcock T. Peri-operative management of the surgical patient with diabetes 2015: Association of Anaesthetists of Great Britain and Ireland. Anaesthesia. 2015 Dec;70(12):1427-40. doi: 10.1111/anae.13233. Epub 2015 Sep 29.

  PMID: 26417892 BACKGROUND

• Smith BK, Ford RJ, Desjardins EM, Green AE, Hughes MC, Houde VP, Day EA, Marcinko K, Crane JD, Mottillo EP, Perry CG, Kemp BE, Tarnopolsky MA, Steinberg GR. Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-beta1. Diabetes. 2016 Nov;65(11):3352-3361. doi: 10.2337/db16-0564. Epub 2016 Aug 23.

  PMID: 27554471 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Hyperglycemia; Postoperative Complications

Interventions

Metformin; salicylsalicylic acid

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Patients will be randomized on the day of their pre-operative assessment by our department statistician using a computer-generated table, with an allocation ratio of 1:1:1 in random permuted blocks of 3 or 6. Only the pharmacist and statistician will know the allocation sequence. Concealed medications (over-encapsulated) will be provided to the RC upon confirming the allotment with a unique identification number (UIN), recorded on the patient-specific case record form (CRF).
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Parallel, placebo-controlled trial with block randomization

Study Record Dates

• First Submitted: January 18, 2019
• First Posted: January 25, 2019
• Study Start: December 1, 2023
• Primary Completion: June 1, 2024
• Study Completion: December 1, 2024
• Last Updated: January 13, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share