Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

Abstract

The current preoperative recommendation for the inpatient population regarding use of non-insulin glucose-lowering treatment is to withhold this medication on the day of surgery.1American Diabetes AssociationDiabetes care in the hospital.Diabetes Care. 2018; 41: S144-S151Crossref PubMed Scopus (124) Google Scholar,2Dhatariya K. Levy N. Kilvert A. et al.NHS Diabetes guideline for the perioperative management of the adult patient with diabetes.Diabet Med. 2012; 29: 420-433Crossref PubMed Scopus (173) Google Scholar The reasons are variable for different preparations and involve the risks of hypoglycaemia, lactic acidosis, and keto-acidosis.3Thiruvenkatarajan V. Meyer E.J. Nanjappa N. Van Wijk R.M. Jesudason D. Perioperative diabetic ketoacidosis associated with sodium-glucose co-transporter-2 inhibitors: a systematic review.Br J Anaesth. 2019; 123: 27-36Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Until recently, all these drugs had short half-lives, were taken once or multiple times daily, and were eliminated from the body within 1 day. This enabled the one-size-fits-all recommendation that is now well-known and followed.4Hulst A.H. Hermanides J. Hollmann M.W. DeVries J.H. Preckel B. Lack of consensus on the peri-operative management of patients with diabetes mellitus.Eur J Anaesthesiol. 2019; 36: 168-169Crossref PubMed Scopus (4) Google Scholar However, recent advances in diabetes treatment include once-weekly preparations of long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs). This prompts anaesthesiologists to reconsider their current practice of stopping all antidiabetic medications on the morning of surgery. We argue that the benefits of perioperative continuation outweigh the risk of withholding these medications, and therefore propose a non-withholding policy for all GLP-1 RAs. We focus on the new antidiabetic medication class of GLP-1 RAs (named -natide or -glutide, e.g. exenatide/liraglutide), not to be confused with the recently introduced sodium glucose co-transporter-2 inhibitors (names ending in -gliflozin, e.g. empagliflozin). Although their cardio-reno-protective properties might harbour perioperative potential,5Hulst A.H. Hermanides J. DeVries J.H. Preckel B. Potential benefits of sodium-glucose cotransporter-2 inhibitors in the perioperative period.Anesth Analg. 2018; 127: 306-307Crossref PubMed Scopus (1) Google Scholar they are generally recommended to be withheld before surgery, until more data on perioperative safety are known.6Bardia A. Wai M. Fontes M.L. Sodium-glucose cotransporter-2 inhibitors: an overview and perioperative implications.Curr Opin Anaesthesiol. 2019; 32: 80-85Crossref PubMed Scopus (15) Google Scholar Endogenous GLP-1 is a gut-derived incretin hormone that reduces glycaemia by stimulating insulin production and secretion from pancreatic beta cells and by reducing glucagon secretion from alpha cells.7Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar In addition, GLP-1 inhibits gastric emptying, and reduces appetite and food intake which contribute to glucose lowering.7Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar,8Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.Nat Rev Endocrinol. 2012; 8: 728-742Crossref PubMed Scopus (749) Google Scholar Importantly, the pancreatic effects of GLP-1 only operate during hyperglycaemia, making the risk for hypoglycaemia extremely low.7Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar Endogenous GLP-1 has a half-life of several minutes and is rapidly broken down by dipeptidyl peptidase-4 (DPP-4). The first generation of GLP-1 RAs (e.g. exenatide, lixisenatide) were designed to resist DPP-4-breakdown and could be administered either once or twice daily.8Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.Nat Rev Endocrinol. 2012; 8: 728-742Crossref PubMed Scopus (749) Google Scholar Second-generation GLP-1 RAs (e.g. liraglutide, dulaglutide) have a higher protein-binding, thereby reducing their renal clearance, and further prolonging their half-life.8Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.Nat Rev Endocrinol. 2012; 8: 728-742Crossref PubMed Scopus (749) Google Scholar In the last decade, GLP-1 RAs came to the market as a second-line treatment option for type 2 diabetes mellitus.7Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar Besides established efficacy in improving glucose control, enthusiasm for these medications increased with the findings of large cardiovascular outcome trials.9Pfeffer M.A. Claggett B. Diaz R. et al.Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.N Engl J Med. 2015; 373: 2247-2257Crossref PubMed Scopus (1413) Google Scholar, 10Marso S.P. Daniels G.H. Brown-Frandsen K. et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322Crossref PubMed Scopus (3598) Google Scholar, 11Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (2459) Google Scholar, 12Holman R.R. Bethel M.A. Mentz R.J. et al.Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2017; 377: 1228-1239Crossref PubMed Scopus (968) Google Scholar, 13Hernandez A.F. Green J.B. Janmohamed S. et al.Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.Lancet. 2018; 392: 1519-1529Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar, 14Gerstein H.C. Colhoun H.M. Dagenais G.R. et al.Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.Lancet. 2019; 394: 121-130Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar The long-term cardiovascular outcome trials with GLP-1 RAs were designed to prove cardiovascular safety. All these trials confirmed that GLP-1 RAs were safe and did not increase the long-term risk of major cardiovascular adverse events (MACE).15Holst J.J. Long-acting glucagon-like peptide-1 receptor agonist – status December 2018.Ann Transl Med. 2019; 7 (83–3)Crossref PubMed Google Scholar What was even more important from these reports is that several studies actually showed a reduction in risk of MACE with GLP-1 RAs compared with standard treatment. The currently available preparations, their characteristics, and the most important findings from the respective cardiovascular outcome trials are summarised in Table 1.Table 1Overview of currently available glucagon-like peptide-1 receptor agonists. ∗For superiority. †Originally a once-daily formulation, now available as prolonged release injection for once-weekly. CI, confidence interval; HR, hazard ratio.Duration of actionEffectivenessReferenceDrugHalf-lifeDosing frequencyHbA1c lowering mmol mol−1Major adverse cardiovascular events (MACE)Cardiovascular outcome trialLixisenatide2.5 hDaily 10–20 μg3 (2–3)Non-inferior to placebo (HR=1.02, 95% CI=0.89–1.17, P=0.81∗)ELIXA8Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.Nat Rev Endocrinol. 2012; 8: 728-742Crossref PubMed Scopus (749) Google ScholarExenatide3 hTwice daily 5–10 μg/weekly 2 mg†8 (7–8)Non-inferior to placebo (HR=0.91, 95% CI=0.83–1.00, P=0.06∗)EXSCEL11Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (2459) Google ScholarLiraglutide12.5 hDaily 1.8 mg5 (4–5)Superior to placebo (HR=0.87, 95% CI=0.78–0.97, P=0.01∗)LEADER9Pfeffer M.A. Claggett B. Diaz R. et al.Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.N Engl J Med. 2015; 373: 2247-2257Crossref PubMed Scopus (1413) Google ScholarAlbiglutide5 daysWeekly 30–50 mg8 (7–8)Superior to placebo (HR=0.78, 95% CI=0.68–0.90, P=0.006∗)HARMONY12Holman R.R. Bethel M.A. Mentz R.J. et al.Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2017; 377: 1228-1239Crossref PubMed Scopus (968) Google ScholarDulaglutide5 daysWeekly 1.5 mg7 (6–7)Superior to placebo (HR=0.88, 95% CI=0.79–0.99, P=0.026∗)REWIND13Hernandez A.F. Green J.B. Janmohamed S. et al.Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.Lancet. 2018; 392: 1519-1529Abstract Full Text Full Text PDF PubMed Scopus (716) Google ScholarSemaglutide7 daysWeekly 0.5–1.0 mg11 (10–12)Superior to placebo (HR=0.74, 95% CI=0.58–0.95, P=0.02∗)SUSTAIN-610Marso S.P. Daniels G.H. Brown-Frandsen K. et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322Crossref PubMed Scopus (3598) Google Scholar Open table in a new tab The observed cardioprotective effects of GLP-1 RAs have resulted in extensive research on their effects on cardiovascular physiology, with many postulated mechanisms.16Giblett J.P. Clarke S.J. Dutka D.P. Hoole S.P. Glucagon-like peptide-1: a promising agent for cardioprotection during myocardial ischemia.JACC Basic Transl Sci. 2016; 1: 267-276Crossref PubMed Scopus (17) Google Scholar The most consistently reported finding is the expression of GLP-1 receptors in the sinoatrial node.15Holst J.J. Long-acting glucagon-like peptide-1 receptor agonist – status December 2018.Ann Transl Med. 2019; 7 (83–3)Crossref PubMed Google Scholar Although this explains the increased HR found in all studies administering GLP-1 RAs, it is unlikely to be the explanation for any of the cardioprotective properties.15Holst J.J. Long-acting glucagon-like peptide-1 receptor agonist – status December 2018.Ann Transl Med. 2019; 7 (83–3)Crossref PubMed Google Scholar,17Hulst A.H. Visscher M.J. Cherpanath T.G.V. et al.Effects of liraglutide on myocardial function after cardiac surgery: a secondary analysis of the randomised controlled GLOBE trial.J Clin Med. 2020; 9: 673Crossref Scopus (3) Google Scholar Thus far, cardioprotective mechanisms are poorly understood. Animal studies showed increases in myocardial metabolic efficiency of glucose usage, lower vascular resistances in pulmonary and systemic circulations, and activation of ischaemic preconditioning pathways.16Giblett J.P. Clarke S.J. Dutka D.P. Hoole S.P. Glucagon-like peptide-1: a promising agent for cardioprotection during myocardial ischemia.JACC Basic Transl Sci. 2016; 1: 267-276Crossref PubMed Scopus (17) Google Scholar,17Hulst A.H. Visscher M.J. Cherpanath T.G.V. et al.Effects of liraglutide on myocardial function after cardiac surgery: a secondary analysis of the randomised controlled GLOBE trial.J Clin Med. 2020; 9: 673Crossref Scopus (3) Google Scholar In humans, the relevance of these findings remains unclear, despite some promising results of improved left ventricular function and reduced infarct size after ischaemic injury in GLP-1 RA-treated subjects.18Nikolaidis L.A. Mankad S. Sokos G.G. et al.Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.Circulation. 2004; 109: 962-965Crossref PubMed Scopus (745) Google Scholar,19Read P.A. Khan F.Z. Dutka D.P. Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease.Heart. 2012; 98: 408-413Crossref PubMed Scopus (86) Google Scholar What remains, however, are the findings from major cardiovascular outcome trials (Table 1) that found clear cardiovascular benefits with reduced rates of myocardial infarction, stroke, and revascularisation procedures.10Marso S.P. Daniels G.H. Brown-Frandsen K. et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322Crossref PubMed Scopus (3598) Google Scholar,11Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (2459) Google Scholar,13Hernandez A.F. Green J.B. Janmohamed S. et al.Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.Lancet. 2018; 392: 1519-1529Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar,14Gerstein H.C. Colhoun H.M. Dagenais G.R. et al.Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.Lancet. 2019; 394: 121-130Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar The most commonly reported side-effects of GLP-1 RAs are gastrointestinal, such as nausea, vomiting, and diarrhoea.7Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar In the SUSTAIN trial, 52% of patients reported gastrointestinal side-effects in those receiving semaglutide compared with 35% in the placebo group, resulting in discontinuation of medication in 14% and 8% of patients, respectively.11Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (2459) Google Scholar Nausea and vomiting are explained by direct central effects of GLP-1 and delayed gastric emptying. Both effects decrease over time with ongoing treatment because of tolerance and tachyphylaxis.8Meier J.J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.Nat Rev Endocrinol. 2012; 8: 728-742Crossref PubMed Scopus (749) Google Scholar,20Deane A.M. Chapman M.J. Fraser R.J. et al.The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study.Crit Care. 2009; 13: R67Crossref PubMed Scopus (68) Google Scholar, 21Plummer M.P. Jones K.L. Annink C.E. et al.Glucagon-like peptide 1 attenuates the acceleration of gastric emptying induced by hypoglycemia in healthy subjects.Diabetes Care. 2014; 37: 1509-1515Crossref PubMed Scopus (27) Google Scholar, 22Umapathysivam M.M. Lee M.Y. Jones K.L. et al.Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia.Diabetes. 2014; 63: 785-790Crossref PubMed Scopus (83) Google Scholar, 23Meier J.J. Rosenstock J. Hincelin-Méry A. et al.Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial.Diabetes Care. 2015; 38: 1263-1273Crossref PubMed Scopus (176) Google Scholar, 24Nauck M.A. Kemmeries G. Holst J.J. Meier J.J. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans.Diabetes. 2011; 60: 1561-1565Crossref PubMed Scopus (241) Google Scholar After 8 weeks of treatment with liraglutide (a long-acting GLP-1 RA), gastric emptying returned to near baseline values.23Meier J.J. Rosenstock J. Hincelin-Méry A. et al.Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial.Diabetes Care. 2015; 38: 1263-1273Crossref PubMed Scopus (176) Google Scholar Of note, contrasting effects have been found with shorter acting GLP-1 RAs that retained delayed gastric emptying over time.23Meier J.J. Rosenstock J. Hincelin-Méry A. et al.Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial.Diabetes Care. 2015; 38: 1263-1273Crossref PubMed Scopus (176) Google Scholar Although associated with reduced oral intake and a beneficial loss of weight in overweight and obese patients, these effects might worry anaesthesiologists given the theoretically increased risk of aspiration. However, although commonly reported by patients, these symptoms are mostly mild, are rarely a reason for discontinuation of therapy, and seem to decrease over time with ongoing treatment.7Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Abstract Full Text Full Text PDF PubMed Scopus (2904) Google Scholar,25Nauck M. Hompesch M. Filipczak R. et al.Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes.Exp Clin Endocrinol Diabetes. 2006; 114: 417-423Crossref PubMed Scopus (138) Google Scholar, 26Lean M.E. Carraro R. Finer N. et al.Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults.Int J Obes. 2014; 38: 689-697Crossref PubMed Scopus (114) Google Scholar, 27Kendall D.M. Riddle M.C. Rosenstock J. et al.Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.Diabetes Care. 2005; 28: 1083-1091Crossref PubMed Scopus (1075) Google Scholar Although gastrointestinal side-effects occurred commonly in the large cardiovascular outcome trials, most were reported in the first weeks after initiation and they only led to discontinuation of treatment in 1–3% of cases.10Marso S.P. Daniels G.H. Brown-Frandsen K. et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322Crossref PubMed Scopus (3598) Google Scholar,11Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (2459) Google Scholar On the ICU, GLP-1 was also found to decrease gastric motility, although its effect was minimal when gastric emptying was already delayed.28Deane A.M. Chapman M.J. Fraser R.J. et al.Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia.Crit Care Med. 2010; 38: 1261-1269Crossref PubMed Scopus (76) Google Scholar In patients with diabetes mellitus, gastroparesis is a known complication that requires attention and appropriate action by anaesthesiologists. Postoperatively, gastrointestinal upset remains a common concern. Despite the fact that surprisingly few perioperative studies recorded this outcome,29Hulst A.H. Plummer M.P. Hollmann M.W. et al.Systematic review of incretin therapy during peri-operative and intensive care.Crit Care. 2018; 22: 1-12Crossref PubMed Scopus (11) Google Scholar it is reassuring that GLP-1 RAs do not appear to further increase the risk of postoperative nausea and vomiting.30Polderman J.A.W. van Steen S.C.J. Thiel B. et al.Peri-operative management of patients with type-2 diabetes mellitus undergoing non-cardiac surgery using liraglutide, glucose–insulin–potassium infusion or intravenous insulin bolus regimens: a randomised controlled trial.Anaesthesia. 2018; 73: 332-339Crossref PubMed Scopus (21) Google Scholar, 31Hulst A.H. Visscher M.J. Godfried M.B. et al.Liraglutide for perioperative management of hyperglycaemia in cardiac surgery patients: a multicentre randomized superiority trial.Diabetes Obes Metab. 2020; 22: 557-565Crossref PubMed Scopus (9) Google Scholar, 32Besch G. Perrotti A. Mauny F. et al.Clinical effectiveness of intravenous exenatide infusion in perioperative glycemic control after coronary artery bypass graft surgery.Anesthesiology. 2017; 127: 775-787Crossref PubMed Scopus (16) Google Scholar We performed two randomised trials studying preoperative liraglutide administration, including more than 400 patients. In both trials, the liraglutide intervention group did not report higher rates of nausea or vomiting compared with the non-GLP-1 groups, neither before nor after surgery. Several recent studies investigated different GLP-1 RAs in the perioperative period, showing their efficacy in improving glycaemic control.29Hulst A.H. Plummer M.P. Hollmann M.W. et al.Systematic review of incretin therapy during peri-operative and intensive care.Crit Care. 2018; 22: 1-12Crossref PubMed Scopus (11) Google Scholar The first two studies used a continuous infusion of GLP-1 during coronary artery bypass grafting (CABG) which resulted in lower perioperative glucose concentrations.33Sokos G.G. Bolukoglu H. German J. et al.Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting.Am J Cardiol. 2007; 100: 824-829Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar,34Kohl B.A. Hammond M.S. Cucchiara A.J. Ochroch E.A. Intravenous GLP-1 (7-36) amide for prevention of hyperglycemia during cardiac surgery: a randomized, double-blind, placebo-controlled study.J Cardiothorac Vasc Anesth. 2014; 28: 618-625Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar A continuous i.v. infusion of exenatide (first generation, short-acting GLP-1 RA) during CABG also reduced blood glucose concentrations and insulin requirements, during and after surgery.32Besch G. Perrotti A. Mauny F. et al.Clinical effectiveness of intravenous exenatide infusion in perioperative glycemic control after coronary artery bypass graft surgery.Anesthesiology. 2017; 127: 775-787Crossref PubMed Scopus (16) Google Scholar,35Lipš M. Mráz M. Kloučková J. et al.The effect of continuous exenatide infusion on cardiac function and perioperative glucose control in cardiac surgery patients: a single-blind, randomized, controlled trial.Diabetes Obes Metab. 2017; 19: 1818-1822Crossref PubMed Scopus (13) Google Scholar Of note, GLP-1 RAs have only been approved for s.c. administration. Liraglutide (second generation, once-daily GLP-1 RA) administered before surgery was effective in lowering glucose and insulin requirements in cardiac surgery and in patients undergoing noncardiac surgery.30Polderman J.A.W. van Steen S.C.J. Thiel B. et al.Peri-operative management of patients with type-2 diabetes mellitus undergoing non-cardiac surgery using liraglutide, glucose–insulin–potassium infusion or intravenous insulin bolus regimens: a randomised controlled trial.Anaesthesia. 2018; 73: 332-339Crossref PubMed Scopus (21) Google Scholar,31Hulst A.H. Visscher M.J. Godfried M.B. et al.Liraglutide for perioperative management of hyperglycaemia in cardiac surgery patients: a multicentre randomized superiority trial.Diabetes Obes Metab. 2020; 22: 557-565Crossref PubMed Scopus (9) Google Scholar In these studies, adverse events have only been recorded as secondary outcomes, yet no signal of harm has been detected. A recent systematic review and meta-analysis of perioperative trials studying GLP-1 RAs found improved perioperative glycaemic control without increasing the incidence of hypoglycaemia.29Hulst A.H. Plummer M.P. Hollmann M.W. et al.Systematic review of incretin therapy during peri-operative and intensive care.Crit Care. 2018; 22: 1-12Crossref PubMed Scopus (11) Google Scholar In some specific situations, stopping GLP-1 RAs in patients already taking these should be considered. Post-marketing surveillance reported a possible association between GLP-1 treatment and pancreatitis or pancreatic cancer. However, analysis of all large-scale cardiovascular outcome trials found no increased risk of pancreas pathology. Nonetheless, stopping GLP-1 in patients undergoing pancreatic surgery or with postoperative pancreatitis must be considered. Furthermore, although GLP-1 RAs are safe for use in patients with impaired kidney function, they should be stopped in case of acute kidney injury requiring renal replacement therapy. Finally, we suggest that GLP-1 RAs should be stopped in case of postoperative ileus because of its effects on gastric motility, even though delayed gastric emptying is a problem during therapy initiation that abates over time. No perioperative study has yet been performed using a once-weekly GLP-1 RA, although at least one is underway administering dulaglutide before cardiac surgery (NCT 03743025). Nonetheless, use of GLP-1 RAs in patients with diabetes mellitus is growing. As a result, anaesthesiologists will increasingly encounter these medications in their patients. With the introduction of the newer long-acting GLP-1 RAs, taken once-weekly, the advice to withhold antihyperglycaemic treatment preoperatively needs to be reconsidered. Firstly, to stop long-acting GLP-1 RAs before surgery is impractical. Effective discontinuation would require stopping ≥2 weeks in advance, affecting glycaemic control for a similar period. As patients are often seen only shortly before surgery, this policy could lead to unnecessary postponement of surgery. In addition, worse preoperative glycaemic control is associated with a higher risk of postoperative complications.36Iavazzo C. McComiskey M. Datta M. et al.Preoperative HBA1c and risk of postoperative complications in patients with gynaecological cancer.Arch Gynecol Obstet. 2016; 294: 161-164Crossref PubMed Scopus (12) Google Scholar,37Kotagal M. Symons R.G. Hirsch I.B. et al.Perioperative hyperglycemia and risk of adverse events among patients with and without diabetes.Ann Surg. 2015; 261: 97-103Crossref PubMed Scopus (182) Google Scholar Secondly, continuation of GLP-1 RAs perioperatively is likely a safe practice. GLP-1 improves glycaemic control by reducing the incidence of hyperglycaemia without increasing hypoglycaemia. Few side-effects have been reported and most are mild. Although anaesthesiologists should be aware of the theoretical side-effects such as delayed gastric emptying and possible nausea and vomiting, GLP-1 RAs can be considered safe and effective in the perioperative period. Although shorter-acting preparations could be withheld, we recommend continuing all GLP-1 RAs throughout the perioperative period. As this is in line with the Association of Anaesthetists for day-case surgery,38Bailey C.R. Ahuja M. Bartholomew K. et al.Guidelines for day-case surgery 2019: guidelines from the association of Anaesthetists and the British association of day surgery.Anaesthesia. 2019; 74: 778-792Crossref PubMed Scopus (60) Google Scholar we extend this recommendation from ambulatory surgery to all perioperative patients. Experts have highlighted the potentially advantageous aspects of using GLP-1 RAs for the in-hospital treatment of hyperglycaemia,39Umpierrez G.E. Korytkowski M. Is incretin-based therapy ready for the care of hospitalized patients with type 2 diabetes?.Diabetes Care. 2013; 36: 2112-2117Crossref PubMed Scopus (36) Google Scholar,40Mustafa O.G. Whyte M.B. The use of GLP-1 receptor agonists in hospitalised patients: an untapped potential.Diabetes Metab Res Rev. 2019; 35e3191Crossref PubMed Scopus (9) Google Scholar and several studies have shown this to be a safe and effective adjunct for in-hospital glucose control.30Polderman J.A.W. van Steen S.C.J. Thiel B. et al.Peri-operative management of patients with type-2 diabetes mellitus undergoing non-cardiac surgery using liraglutide, glucose–insulin–potassium infusion or intravenous insulin bolus regimens: a randomised controlled trial.Anaesthesia. 2018; 73: 332-339Crossref PubMed Scopus (21) Google Scholar,31Hulst A.H. Visscher M.J. Godfried M.B. et al.Liraglutide for perioperative management of hyperglycaemia in cardiac surgery patients: a multicentre randomized superiority trial.Diabetes Obes Metab. 2020; 22: 557-565Crossref PubMed Scopus (9) Google Scholar,41Fayfman M. Galindo R.J. Rubin D.J. et al.A randomized controlled trial on the safety and efficacy of exenatide therapy for the inpatient management of general medicine and surgery patients with type 2 diabetes.Diabetes Care. 2019; 42: 450-456Crossref PubMed Scopus (26) Google Scholar In line with the arguments for preoperative continuation, continuation of GLP-1 RAs during hospital stay should also be considered. Perioperative studies of long-acting GLP-1 RAs showed better glycaemic control compared with placebo or standard care with insulin in the perioperative period without a higher risk for developing hypoglycaemia. Side-effects, most frequently gastrointestinal in nature, are mostly mild and diminish over time. Historically, non-insulin glucose-lowering medications are stopped on the day of surgery. However, stopping these once weekly preparations would require stopping the medication several weeks preoperatively. This is not only impractical but would also lead to inadequate glycaemic control for a prolonged period. In light of the current evidence, continuation of these drugs is a safe and effective practice with regard to glycaemic control and side-effects. We therefore recommend that all GLP-1 RAs be continued during the perioperative period.