CLINICAL FOCUS REVIEW Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M., Editor Perioperative Management of Oral Glucose-lowering Drugs in the Patient with Type 2 Diabetes Jean-Charles Preiser, M.D., Ph.D., Bruna Provenzano, M.D., Wasineeart Mongkolpun, M.D., Katarina Halenarova, M.D., Miriam Cnop, M.D., Ph.D. iabetes mellitus is a group of metabolic disorders, urgent cholecystectomy in insulin-requiring diabetic patients characterized by hyperglycemia, resulting from rela- than in orally treated diabetic patients, possibly pointing to D Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/133/2/430/514400/20200800.0-00029.pdf by guest on 02 October 2021 tive insulin deficiency, often on a background of insulin worse outcomes in people with more advanced diabetes resistance (type 2 diabetes), or (near) absolute insulin defi- and/or more severe comorbidities. ciency related to autoimmune pathophysiology (type 1 dia- Surgical stress induces insulin resistance and increased betes). The most common form is type 2 diabetes, and its endogenous glucose production, resulting in stress hyper- global prevalence is rising as a result of changes in lifestyle glycemia characterized by blood glucose level greater than and lengthening of life expectancy.1,2 An estimated 463 mil- 180 mg/dl (10 mM).15–18 When this persists, elevated glucose lion people aged 20 to 79 yr have diabetes,3 which cor- levels become deleterious, promoting immune dysfunction responds to 9.3% of the adult population and represents and susceptibility to infections, endothelial dysfunction and a four-fold increase in diabetes prevalence since 1980.4 thrombosis that can culminate in stroke and acute myo- Patients with type 2 diabetes often have comorbidities such cardial infarction, and oxidative stress caused by enhanced as arterial hypertension, obesity, ischemic heart disease, renal reactive oxygen species production.19 failure, and atherosclerosis. Ischemic heart disease in partic- In the intensive care setting, stress hyperglycemia, spon- ular may affect younger patients compared to nondiabetic taneous or drug-related hypoglycemia (glucose less than populations and may have silent ischemia. Hence, assessing 70 mg/dl [3.89 mM]) and high glycemic variability (coef- the preoperative risk of diabetic patients is challenging, and ficient of variation greater than 20%) constitute the three can be underestimated. As shown outside the perioperative features of dysglycemia syndrome. All are associated with setting, these patients have equivalent or higher risk for worse outcomes in acutely injured patients.20–22 Badawi et cardiovascular events and mortality as patients with typical al.22 analyzed a large cohort of critically ill patients from angina.5,6 However, current guidelines recommend against 344 American intensive care units to evaluate the associa- systematic stress testing in individuals without symptoms.7,8 tion between intensive care unit–acquired dysglycemia and The number of type 2 diabetes patients undergoing sur- in-hospital mortality. The results showed that hypoglycemia gical procedures is rising worldwide. An American review as well as hyperglycemia and glucose variability are delete- from 2004 estimated that 15 to 20% of surgical patients are rious to critically ill patients. The longer the duration of this diabetic.4 Twenty-five percent of type 2 diabetes patients will variability, the greater is the impact on in-hospital mortality. require a surgical procedure during their lifetime9 related to The adjusted relative risk (95% CI) of mortality for hyper- chronic complications that affect the cardiovascular, ophthal- glycemia (glucose, 180 to 240 mg/dl [10 to 13.3 mM]) was mologic, renal or orthopedic systems. The risk of postoper- 1.63 (1.47 to 1.81). The relative risk for glycemic variability ative complications (i.e., gastroparesis, cardiovascular events, was 1.61 (1.47 to 1.78), and for hypoglycemia (glucose, 40 and postoperative infection) in type 2 diabetes patients is to 60 mg/dl [2.2 to 3.3 mM]) it was 1.53 (1.37 to 1.70). higher than in nondiabetic patients, as reported by large-scale The optimal glycemic control in diabetic patients should studies.4,5,9–12 In order to adjust for potential confounders, the also consider the prior level of glucose control, indicated by adverse outcomes occurring after major surgery have been the level of glycated hemoglobin. The “stress hyperglycemia compared with a propensity-matched cohort of non-diabetic ratio” and the “glycemic ratio” were introduced to calcu- patients in a cohort of more than 33,000 patients in Taiwan.13 late the difference between actual and average glycemia.23,24 In this study, Lin et al. found a higher risk of postoperative The estimated average glucose value derived from glycated sepsis (odds ratio, 1.33; 95% CI, 1.01 to 1.74) and in-hospital hemoglobin could be the optimal target range, as suggested mortality (odds ratio, 1.51; 95% CI, 1.07 to 2.13) when com- by reports of lower mortality or reduced need for inten- pared to nondiabetic patients. Karamanos et al.14 demonstrated sive care when glucose was closer to the average value.23,24 higher mortality, cardiovascular and renal complications after In surgical intensive care patients, and in particular for This article has been selected for the Anesthesiology CME Program. Learning objectives and disclosure and ordering information can be found in the CME section at the front of this issue. This article is featured in “This Month in Anesthesiology,” page 1A. Submitted for publication August 30, 2019. Accepted for publication February 11, 2020. Published online first on March 12, 2020. From the Departments of Intensive Care (J.-C.P., B.P., W.M., K.H.) and Anesthesiology (K.H.), Erasmus Hospital, the Division of Endocrinology (M.C.), and the Center for Diabetes Research (M.C.), Free University of Brussels, Brussels, Belgium. Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved. Anesthesiology 2020; 133:430–8. DOI: 10.1097/ALN.0000000000003237 430 AUGUST 2020 ANESTHESIOLOGY, V 133 • NO 2 Copyright © 2020, the American Society of Anesthesiologists, Inc. Unauthorized reproduction of this article is prohibited. Perioperative Management of Glucose-lowering Drugs scheduled surgeries, perioperative care should focus on the long-acting insulin secretagogues. Meglitinides constitute prevention of dysglycemia in order to improve outcomes. another class of insulin secretagogues that are taken with The proper management of oral glucose-lowering treat- meals and are more rapid and short-acting. The currently ment in type 2 diabetic patients is therefore crucial. available second generation sulfonylurea include gliclazide, glimepiride and glyburide or glibenclamide. The megli- New Oral Glucose-lowering Drugs tinides include repaglinide and nateglinide. These drugs bind the sulfonylurea receptor, and thereby close potassium Type 2 diabetes treatment has undergone major changes adenosine triphosphate channels in pancreatic β cells, result- with the development of new drug classes, such as sodi- ing in membrane depolarization, calcium influx and insu- um-glucose cotransporter-2 inhibitors, and demonstra- lin release. The American Diabetes Association (Arlington, tion of their safety and efficacy in large-scale clinical trials. Virginia) recommends sulfonylurea or meglitinides as In recent trials primary outcomes were cardiovascular, Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/133/2/430/514400/20200800.0-00029.pdf by guest on 02 October 2021 add-on oral treatment when metformin does not suffice, whereas the primary outcome of previous trials was gly- in the absence of atherosclerotic cardiovascular disease or cemic control.25 This change in paradigm was mandated by chronic kidney disease. the United States Food and Drug Administration, which, Clinical studies assessed the efficacy of sulfonylurea since 2008, has required data on cardiovascular safety for on glycemic control.28 A meta-analysis of 31 trials with a new glucose-lowering drugs, after the finding increased median 16-week duration of showed that sulfonylurea in rates of myocardial infarction and cardiovascular mortality mono- or combination therapy with another drug low- in patients randomized to rosiglitazone in a meta-analysis of 42 studies.26 These changes show the complexity of oral ered glycated hemoglobin by 1.5% (17 mmol/mol; 95% glucose-lowering drug use in type 2 diabetic patients. CI, 1.3 to 1.8) and 1.6% (18 mmol/mol; 95% CI, 1.0 to In practice, the current recommendations for the man- 2.2), respectively. Sulfonylurea are cheaper than other oral agement of type 2 diabetes are simple for the initiation of glucose-lowering drugs recommended as second step. pharmacologic treatment: metformin is the first agent to be Meglitinides were mostly tested as an adjunctive therapy to started, unless contraindicated (such as a reduction in glo- metformin, and combination therapy safely improved gly- 29 merular filtration rate less than 30 ml/min). Therapeutic effi- cemic control (meta-analysis of 22 trials). cacy is monitored by the level of glycated hemoglobin. Once As the effects of sulfonylurea are independent of metformin is no longer sufficient despite adequate dosing, a circulating glucose levels, there is an increased risk of second oral medication (e.g., sulfonylurea, thiazolidinedione, hypoglycemic events. The rate of hypoglycemia was a sodium-glucose cotransporter-2 inhibitor, a dipeptidyl increased by 2.4-fold in patients treated with sulfony- 28 peptidase-4 inhibitor) or a glucagon-like peptide 1 analog lurea as compared with other glucose-lowering agents. should be selected, taking into consideration the individual This risk can further increase in the hospital, as a result patient’s risk of atherosclerotic cardiovascular disease, heart of differences between hospital diets and usual dietary failure, or chronic kidney disease.27 If combination ther- habits. Hypoglycemia appears to be less of a risk for 30 apy does not suffice, combination therapy with a third oral meglitinides but still is relatively high. Besides the glucose-lowering drug or insulin must be considered.