Perioperative medicine training resources: U3M10: The optimisation of pre-diabetes and diabetes

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are oral medications that promote glucose excretion in the urine for the treatment of type 2 diabetes. Note that SGLT2i are not approved for use in the management of type 1 diabetes in Australia or New Zealand, although they are sometimes used off-label in this setting.

Abstract
Objective: To determine the prevalence of diabetes in inpatients in Melbourne hospitals.

Design: Point prevalence survey of all inpatients in each hospital on a single day between 30 November 2010 and 22 November 2012.

Setting: 11 hospitals in metropolitan Melbourne including community, secondary and tertiary hospitals and one aged care and rehabilitation centre.

Participants: 2308 adult inpatients in all wards apart from intensive care, emergency, obstetrics and psychiatry.

Main outcome measures: Point prevalence of self-reported diabetes, details of current medication, self-reported frequency of complications.

Results: Diabetes status was obtained in 2273 of 2308 inpatients (98.5%). Of these, 562 (24.7%) had diabetes (95% CI, 22.9%-26.5%). Diabetes prevalence ranged from 15.7% to 35.1% in different hospitals (P < 0.001). Patients with diabetes were older, heavier and more likely to be taking lipid-lowering, antihypertensive and blood-thinning medications. Of 388 patients with complete medication information, 270 (69.6%) were taking oral hypoglycaemic agents alone or in combination with insulin, 158 (40.7%) were treated with insulin (67 [17.3%] with insulin alone) and 51 (13.1%) were not taking medication for diabetes. The frequency of diabetes complications was very high: 207/290 (71.4%) for any microvascular complication, 275/527 (52.2%) for any macrovascular complication and 227/276 (82.2%) for any complication.

Conclusion: The high burden of diabetes in Melbourne hospital inpatients has major implications for patient health and health care expenditure. Optimising care of these high-risk patients has the potential to decrease inpatient morbidity and length of stay as well as preventing or delaying future complications. A formal Australian national audit of inpatient diabetes would determine its true prevalence and consequences, allowing rational planning to deal with shortcomings in its management.

Abstract
Prediabetes has a high prevalence, with early detection essential to facilitate optimal management to prevent the development of conditions such as type 2 diabetes and cardiovascular disease. Prediabetes can include impaired fasting glucose, impaired glucose tolerance and elevated HbA1c. This position statement outlines the approaches to screening and management of prediabetes in primary care. There is good evidence to implement intensive, structured lifestyle interventions for individuals with impaired glucose tolerance. The evidence for those with impaired fasting glucose or elevated HbA1c is less clear, but individuals should still be provided with generalised healthy lifestyle strategies. A multidisciplinary approach is recommended to implement healthy lifestyle changes through education, nutrition and physical activity. Individuals should aim to lose weight (5-10% of body mass) using realistic and sustainable dietary approaches supported by an accredited practising dietitian, where possible. Physical activity and exercise should be used to facilitate weight maintenance and reduce blood glucose. Moderate-vigorous intensity aerobic exercise and resistance training should be prescribed by an accredited exercise physiologist, where possible. When indicated, pharmacotherapy, metabolic surgery and psychosocial care should be considered, in order to enhance the outcomes associated with lifestyle change. Individuals with prediabetes should generally be evaluated annually for their diabetes status.

Abstract
Objective: Pregnancy has been associated with development and progression of diabetic retinopathy (DR), but incidence of DR remains unclear. We assessed DR progression rate and its predictors during pregnancies in patients with type 1 diabetes.

Research design and methods: We report the retrospective data from pregnancies in patients with type 1 diabetes followed in Lille, France (1997-2015). Eye examination was performed every 3 months or every month in case of severe nonproliferative retinopathy or progression. Progression was defined by DR degradation (≥1 stage of the Early Treatment Diabetic Retinopathy Study [ETDRS] classification); it included DR development and worsening in patients without and with prepregnancy DR, respectively.

Results: A total of 499 pregnancies in 375 patients were included; prepregnancy retinopathy was present in 30.3%. Progression, development, and worsening rates were 21.8%, 24.4% of those without retinopathy, and 15.9% of those with retinopathy, respectively. Development of sight-threatening retinopathy was rare. Progression mainly occurred in early or midpregnancy. Elevated prepregnancy HbA1c and duration of diabetes ≥10 years were predictors of DR progression. Among pregnancies with prepregnancy DR, continuous subcutaneous insulin infusion (CSII) tended to decrease the risk of DR progression. Among CSII-treated patients, those with prepregnancy DR had a significantly decreased risk of DR progression. Among the 270 pregnancies of women with any DR during pregnancy who returned for a postpartum ophthalmologic examination, the rate of progression was only 4.1% and the rate of regression was 9.3%.

Conclusions: This study provides epidemiologic data on progression of retinopathy during pregnancy and will be useful for future guidelines for retinopathy screening.

Abstract
Context: Although random blood glucose (RBG) values are common in clinical practice, the role of elevated RBG values as a risk factor for type 2 diabetes is not well described.

Objective: This study aimed to examine nondiagnostic, RBG values as a risk factor for type 2 diabetes

Design: This was a cross-sectional study of National Health and Nutrition Examination Surveys (NHANES) participants (2005-2010).

Participants: Nonfasting NHANES participants (n = 13 792) without diagnosed diabetes were included.

Primary outcome: The primary outcome was glycemic status (normal glycemia, undiagnosed prediabetes, or undiagnosed diabetes) using hemoglobin HbA1C as the criterion standard.

Analysis: Multinomial logistic regression examined associations between diabetes risk factors and RBG values according to glycemic status. Associations between current U.S. screening strategies and a hypothetical RBG screening strategy with undiagnosed diabetes were examined.

Results: In unadjusted analyses, a single RBG ≥ 100 mg/dL (5.6 mmol/L) was more strongly associated with undiagnosed diabetes than any single risk factor (odds ratio [OR], 31.2; 95% confidence interval [CI], 21.3-45.5) and remained strongly associated with undiagnosed diabetes (OR, 20.4; 95% CI, 14.0-29.6) after adjustment for traditional diabetes risk factors. Using RBG < 100 mg/dL as a reference, the adjusted odds of undiagnosed diabetes increased significantly as RBG increased. RBG 100-119 mg/dL (OR 7.1; 95% CI 4.4-11.4); RBG 120-139 mg/dL (OR 30.3; 95% CI 20.0-46.0); RBG ≥ 140 mg/dL (OR 256; 95% CI 150.0-436.9). As a hypothetical screening strategy, an elevated RBG was more strongly associated with undiagnosed diabetes than current United States Preventative Services Task Force guidelines (hypertension alone; P < .0001) and similar to American Diabetes Association guidelines (P = .12).

Conclusions: A single RBG ≥ 100 mg/dL is more strongly associated with undiagnosed diabetes than traditional risk factors. Abnormal RBG values are a risk factor for diabetes and should be considered in screening guidelines.

Abstract
Objective: To evaluate the effect of preoperative blood glucose (POBG) level on hospital length of stay (LOS) in patients undergoing appendectomy or laparoscopic cholecystectomy.

Research design and methods: We conducted a retrospective cohort study of patients aged ≥18 years who had undergone appendectomy or laparoscopic cholecystectomy procedures between 2005 and 2016 at a tertiary medical center in Taiwan. The association between POBG level and LOS was evaluated using a multivariable quasi-Poisson regression with robust variance. Multiple imputations were performed to replace missing values.

Results: We included 8,291 patients; 4,025 patients underwent appendectomy (appendectomy group) and 4,266 underwent laparoscopic cholecystectomy (laparoscopic cholecystectomy group). In the appendectomy group, patients with POBG levels of ≥123 mg/dL (adjusted relative risk [aRR] 1.19; 95% CI 1.06-1.33) had a 19% higher risk of having a LOS of >3 days than did those with POBG levels of <106 mg/dL. In the laparoscopic cholecystectomy group, patients with POBG levels of ≥128 mg/dL also had a significantly higher risk of having a LOS of >3 days (aRR 1.17; 95% CI 1.07-1.29) than did those with POBG levels of <102 mg/dL. A positive dose-response curve between POBG and an adjusted risk of a LOS of >3 days was observed, although the curve starts to flatten at a POBG level of ∼130 mg/dL.

Conclusions: We demonstrated that a higher POBG level was significantly associated with a prolonged LOS for patients undergoing appendectomy or laparoscopic cholecystectomy. The optimal POBG level may be lower than that commonly perceived.

Abstract
For many years, the diagnosis of diabetes has been made through the laboratory-based measurement of fasting or random blood glucose levels, or using the oral glucose tolerance test. A glycated haemoglobin (HbA(1c)) level ≥ 6.5% (48 mmol/mol) is now also acceptable for diagnosing diabetes. Caution is needed in interpreting HbA(1c) test results in the presence of conditions affecting red blood cells or their survival time, such as haemoglobinopathies or anaemia.

Abstract
Glycated haemoglobin (HbA1c) assessment for the diagnosis of diabetes mellitus overcomes many practical problems associated with traditional blood glucose measurements. However, the test is not without limitations of which the medical practitioner needs to be aware. The possibility of an individual having a medical condition that interferes with the test should always be considered, even though these conditions are rare in most Australian communities. Appropriately used, HbA1c assessment should provide a cost-effective, efficient and simple tool for the early diagnosis of type 2 diabetes.

Abstract
These Joint British Diabetes Societies guidelines, commissioned by NHS Diabetes, for the perioperative management of the adult patient undergoing surgery are available in full in the Supporting Information. This document goes through the seven stages of the patient journey when having surgery. These are: primary care referral; surgical outpatients; preoperative assessment; hospital admission; surgery; post-operative care; discharge. Each stage is given its own considerations, outlining the roles and responsibilities of each group of healthcare professionals. The evidence base for the recommendations made at each stage, discussion of controversial areas and references are provided in the report. This document has two key recommendations. Firstly, that the management of the elective adult surgery patients should be with modification to their usual diabetes treatment if the fasting is minimized because the routine use of a variable rate intravenous insulin infusion is not recommended. Secondly, that poor preoperative glycaemic control leads to post-outcomes and thus, where appropriate, needs to be addressed prior to referral for surgery.

Abstract
Introduction: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as an important class of blood glucose-lowering medications, due to cardiovascular, metabolic, and renal benefits. However, there is a small but significant risk of diabetic ketoacidosis (DKA) associated with their use.

Methods: A literature search was conducted in Ovid MEDLINE and Embase to July 2019 using variants on the key search terms sodium-glucose cotransporter 2, diabetic ketoacidosis, and type 2 diabetes. A broad spectrum of evidence was incorporated to facilitate a comprehensive narrative review. Further sources were identified through hand searching of reference lists.

Discussion: Although cardiovascular outcome trials demonstrated mixed evidence of SGLT2i associated DKA, increasing evidence from case reports and cohort studies has identified an increased risk. SGLT2i use is associated with a ketotic state caused by an increased glucagon:insulin ratio and stimulated by factors including stress-induced hormonal changes, insufficient insulin, decreased glucose, increased ketone resorption, and hypovolemia. Atypical presentations of DKA with lower-than-expected blood glucose levels are possible with SGLT2i use, so clinical and biochemical monitoring is vital for early identification and management. DKA risk is particularly increased with precipitating factors, therefore optimization of risk factors is vital. Recommendations for perioperative and sick day management of patients taking SGLT2i have been suggested based on available evidence.

Conclusion: SGLT2i are an excellent class of drug in the physician's toolkit for managing type 2 diabetes. However, both clinicians and patients must be aware of the potential for DKA and the need for increased monitoring, both clinically and biochemically, when potential precipitating factors are present. In acutely unwell patients, these medications should be withheld to reduce the risk of DKA.

Abstract
Objective: Hospital hyperglycemia, in individuals with and without diabetes, has been identified as a marker of poor clinical outcome in cardiac surgery patients. However, the impact of perioperative hyperglycemia on clinical outcome in general and noncardiac surgery patients is not known.

Research design and methods: This was an observational study with the aim of determining the relationship between pre- and postsurgery blood glucose levels and hospital length of stay (LOS), complications, and mortality in 3,184 noncardiac surgery patients consecutively admitted to Emory University Hospital (Atlanta, GA) between 1 January 2007 and 30 June 2007.

Results: The overall 30-day mortality was 2.3%, with nonsurvivors having significantly higher blood glucose levels before and after surgery (both P < 0.01) than survivors. Perioperative hyperglycemia was associated with increased hospital and intensive care unit LOS (P < 0.001) as well as higher numbers of postoperative cases of pneumonia (P < 0.001), systemic blood infection (P < 0.001), urinary tract infection (P < 0.001), acute renal failure (P = 0.005), and acute myocardial infarction (P = 0.005). In multivariate analysis (adjusted for age, sex, race, and surgery severity), the risk of death increased in proportion to perioperative glucose levels; however, this association was significant only for patients without a history of diabetes (P = 0.008) compared with patients with known diabetes (P = 0.748).

Conclusions: Perioperative hyperglycemia is associated with increased LOS, hospital complications, and mortality after noncardiac general surgery. Randomized controlled trials are needed to determine whether perioperative diabetes management improves clinical outcome in noncardiac surgery patients.

Abstract
Background: Diabetes mellitus is a risk factor for deep sternal wound infection after open heart surgical procedures. We previously showed that elevated postoperative blood glucose levels are a predictor of deep sternal wound infection in diabetic patients. Therefore, we hypothesized that aggressive intravenous pharmacologic control of postoperative blood glucose levels would reduce the incidence of deep sternal wound infection.

Methods: In a prospective study of 2,467 consecutive diabetic patients who underwent open heart surgical procedures between 1987 and 1997, perioperative blood glucose levels were recorded every 1 to 2 hours. Patients were classified into two sequential groups: the control group included 968 patients treated with sliding-scale-guided intermittent subcutaneous insulin injections (SQI); the study group included 1,499 patients treated with a continuous intravenous insulin infusion in an attempt to maintain a blood glucose level of less than 200 mg/dL. There were no differences between these groups with respect to age, sex, procedure, bypass time, antibiotic prophylaxis, or skin preparation methods.

Results: Compared with subcutaneous insulin injections, continuous intravenous insulin infusion induced a significant reduction in perioperative blood glucose levels, which led to a significant reduction in the incidence of deep sternal wound infection in the continuous intravenous insulin infusion group (0.8% [12 of 1,499]) versus the intermittent subcutaneous insulin injection group (2.0% [19 of 968], p = 0.01 by the chi2 test). Multivariate logistic regression revealed that continuous intravenous insulin infusion induced a significant decrease in the risk of deep sternal wound infection (p = 0.005; relative risk, 0.34), whereas obesity (p < 0.03; relative risk, 1.06) and use of an internal thoracic artery pedicle (p = 0.1; relative risk, 2.0) increased the risk of deep sternal wound infection.

Conclusions: Use of perioperative continuous intravenous insulin infusion in diabetic patients undergoing open heart surgical procedures significantly reduces major infectious morbidity and its associated socioeconomic costs.

Abstract
Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects approximately 40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 microg/min and < or =199 microg/min) and macroalbuminuria (UAE > or =200 microg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes.

Abstract
Objective: To identify predictors of postoperative myocardial ischemia in patients scheduled to undergo major noncardiac surgery.

Design: Historical, clinical, laboratory, and physiological data were obtained prospectively before and during surgery to identify potential univariate predictors of postoperative myocardial ischemia, which then were entered into multivariate logistic models. Continuous two-lead electrocardiograms before, during, and after surgery were used to identify episodes of myocardial ischemia.

Setting: Department of Veterans Affairs tertiary care hospital.

Patients: A consecutive sample of 474 men at high risk for or with coronary artery disease who were scheduled to undergo major noncardiac surgery (95% compliance rate).

Main outcome measure: Significant variables identified by multivariate logistic models that are associated with postoperative myocardial ischemia.

Results: Five major preoperative predictors of postoperative myocardial ischemia were identified: (1) left ventricular hypertrophy by electrocardiogram; (2) history of hypertension; (3) diabetes mellitus; (4) definite coronary artery disease; and (5) use of digoxin. The risk of postoperative myocardial ischemia increased progressively with the number of predictors present: in 22% of patients with no predictors, in 31% with one predictor, in 46% with two predictors, in 70% with three predictors, and in 77% with four predictors.

Conclusion: Patients subgroups who are at high risk for developing postoperative myocardial ischemia and who might benefit the most from intensive Holter monitoring in the postoperative period now can be identified preoperatively.

Abstract
Background: Hypoglycemia is a known risk of intensive postoperative glucose control in patients undergoing cardiac operations. However, neither the consequences of hypoglycemia relative to hyperglycemia, nor the possible interaction effects, have been well described. We examined the effects of postoperative hypoglycemia, hyperglycemia, and their interaction on short-term morbidity and mortality.

Methods: Single-institution Society of Thoracic Surgeons (STS) database patient records from 2010 to 2014 were merged with clinical data, including blood glucose values measured in the intensive care unit (ICU). Exclusion criteria included fewer than three glucose measurements and absence of an STS predicted risk of morbidity or mortality score. Primary outcomes were operative mortality and composite major morbidity (permanent stroke, renal failure, prolonged ventilation, pneumonia, or myocardial infarction). Secondary outcomes included ICU and postoperative length of stay. Hypoglycemia was defined as below 70 mg/dL, and hyperglycemia as above 180 mg/dL. Simple and multivariable regression models were used to evaluate the outcomes.

Results: A total of 2,285 patient records met the selection criteria for analysis. The mean postoperative glucose level was 140.8 ± 18.8 mg/dL. Overall, 21.4% of patients experienced a hypoglycemic episode (n = 488), and 1.05% (n = 24) had a severe hypoglycemic episode (<40 mg/dL). The unadjusted odds ratio (UOR) for operative mortality for patients with any hypoglycemic episode compared with those without was 5.47 (95% confidence interval [CI] 3.14 to 9.54), and the UOR for major morbidity was 4.66 (95% CI 3.55 to 6.11). After adjustment for predicted risk of morbidity or mortality and other significant covariates, the adjusted odds (AOR) of operative mortality were significant for patients with any hypoglycemia (AOR 4.88, 95% CI 2.67 to 8.92) and patients with both events (AOR 8.29, 95% CI 1.83 to 37.5) but not hyperglycemia alone (AOR 1.62, 95% CI 0.56 to 4.69). The AOR of major morbidity for patients with both hypoglycemic and hyperglycemic events was 14.3 (95% CI 6.50 to 31.4).

Conclusions: Postoperative hypoglycemia is associated with both mortality and major morbidity after cardiac operations. The combination of both hyperglycemia and hypoglycemia represents a substantial increase in risk. Although it remains unclear whether hypoglycemia is a cause, an early warning sign, or a result of adverse events, this study suggests that hypoglycemia may be an important event in the postoperative period after cardiac operations.

Abstract
Optimal evidence-based perioperative blood glucose control in patients undergoing ambulatory surgical procedures remains controversial. Therefore, the Society for Ambulatory Anesthesia has developed a consensus statement on perioperative glycemic management in patients undergoing ambulatory surgery. A systematic review of the literature was conducted according the protocol recommended by the Cochrane Collaboration. The consensus panel used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for providing suggestions. It was revealed that there is insufficient evidence to provide strong recommendations for the posed clinical questions. In the absence of high-quality evidence, recommendations were based on general principles of blood glucose control in diabetics, drug pharmacology, and data from inpatient surgical population, as well as clinical experience and judgment. In addition, areas of further research were also identified.

Abstract
Background: Diabetes mellitus (DM) is risk factor for complications after orthopedic surgery.

Objectives: We tested the hypothesis that anesthesia preoperative clinic (APC) referral for elevated glycosylated hemoglobin (HbA1c) reduces complication rate after total joint arthroplasty (TJA).

Patients and methods: Patients (n = 203) with and without DM were chosen from 1,237 patients undergoing TJA during 2006 - 12. Patients evaluated in the APC had surgery in 2006 - 8 regardless of HbA1c (uncontrolled). Those evaluated between in subsequent two-year intervals were referred to primary care for HbA1c ≥ 10% and ≥ 8%, respectively, to improve DM control before surgery. Complications and mortality were quantified postoperatively and at three, six, and twelve months. Length of stay (LOS) and patients requiring a prolonged LOS (> 5 days) were recorded.

Results: Patients (197 men, 6 women) underwent 71, 131, and 1 total hip, knee, and shoulder replacements, respectively. Patients undergoing TJA with uncontrolled HbA1c and those with HbA1c < 10%, but not those with HbA1c < 8%, had a higher incidence of coronary disease and hypercholesterolemia than patients without DM. An increase in complication rate was observed in DM patients with uncontrolled HbA1c versus patients without DM (P < 0.001); the complication rate progressively decreased with tighter HbA1c control. More DM patients with preoperative HbA1c that was uncontrolled or ≥ 10% required prolonged LOS versus those without DM (P < 0.001 and P = 0.0404, respectively).

Conclusions: APC referral for elevated HbA1c reduces complication rate and the incidence of prolonged hospitalization during the first year after surgery in diabetics undergoing TJA.

Abstract
Objective: To determine the relationship of perioperative hyperglycemia and insulin administration on outcomes in elective colon/rectal and bariatric operations.

Background: There is limited evidence to characterize the impact of perioperative hyperglycemia and insulin on adverse outcomes in patients, with and without diabetes, undergoing general surgical procedures.

Methods: The Surgical Care and Outcomes Assessment Program is a Washington State quality improvement benchmarking-based initiative. We evaluated the relationship of perioperative hyperglycemia (>180 mg/dL) and insulin administration on mortality, reoperative interventions, and infections for patients undergoing elective colorectal and bariatric surgery at 47 participating hospitals between fourth quarter of 2005 and fourth quarter of 2010.

Results: Of the 11,633 patients (55.4 ± 15.3 years; 65.7% women) with a serum glucose determination on the day of surgery, postoperative day 1, or postoperative day 2, 29.1% of patients were hyperglycemic. After controlling for clinical factors, those with hyperglycemia had a significantly increased risk of infection [odds ratio (OR) 2.0; 95% confidence interval (CI), 1.63-2.44], reoperative interventions (OR, 1.8; 95% CI, 1.41-2.3), and death (OR, 2.71; 95% CI, 1.72-4.28). Increased risk of poor outcomes was observed both for patients with and without diabetes. Those with hyperglycemia on the day of surgery who received insulin had no significant increase in infections (OR, 1.01; 95% CI, 0.72-1.42), reoperative interventions (OR, 1.29; 95% CI, 0.89-1.89), or deaths (OR, 1.21; 95% CI, 0.61-2.42). A dose-effect relationship was found between the effectiveness of insulin-related glucose control (worst 180-250 mg/dL, best <130 mg/dL) and adverse outcomes.

Conclusions: Perioperative hyperglycemia was associated with adverse outcomes in general surgery patients with and without diabetes. However, patients with hyperglycemia who received insulin were at no greater risk than those with normal blood glucoses. Perioperative glucose evaluation and insulin administration in patients with hyperglycemia are important quality targets.

Abstract
Background: The optimal target range for blood glucose in critically ill patients remains unclear.

Methods: Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization.

Results: Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39).

Conclusions: In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987.)

Abstract
Objective: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication.

Research design and methods: Cases identified incidentally are described.

Results: We identified 13 episodes of SGLT-2 inhibitor-associated euDKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers.

Conclusions: SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhibitors should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes.

Abstract
This article forms part of our 'Tests and results' series for 2012, which aims to provide information about common tests that general practitioners order regularly. It considers areas such as indications, what to tell the patient, what the test can and cannot tell you, and interpretation of results.

Abstract
Of 1025 patients (912 men, 113 women) who underwent coronary artery bypass grafting and were followed up for a mean of 7.4 years, 45 (4.4%) had diabetes mellitus. Norwegian population is 1.8-2%). Early mortality was not significantly greater among diabetics than in non-diabetics (2.2 vs. 3.1%, odds ratio--OR-0.44, confidence interval--CI- 0.05-3.56). Diabetic patients had no increased risk of perioperative myocardial infarction (OR = 0.87, CI 0.36-2.10) or of low-output syndrome necessitating intraortic balloon pumping (OR = 0.42, CI 0.55-3.05), and no excess incidence of late non-fatal myocardial infarction (relative risk = 0.69, CI 0.10-1.28) or late chronic heart failure (OR = 2.50, CI 0.5-11.0). Long-term mortality was increased in the diabetic patients (relative risk 1.87, CI 1.60-2.14). Thus diabetes did not entail heightened risk of early mortality, perioperative myocardial infarction or low-output syndrome. Nor was there excess risk of recurrent angina pectoris, late non-fatal myocardial infarction or chronic heart failure among the diabetic patients, but the late mortality risk was increased.

Abstract
Objective: To determine if the improvement in inpatient glycaemic control observed with basal-bolus insulin (BBI) over sliding-scale insulin (SSI) in the formal study setting translates to routine clinical conditions.

Design, setting and patients: Cross-sectional study in which capillary blood glucose levels (BGLs) were prospectively measured four times daily for up to 8 days in 124 patients with type 2 diabetes admitted to a tertiary teaching hospital and treated with BBI between November 2008 and May 2010. Data from the BBI treatment group were compared with retrospective data from 96 patients treated with SSI between June 2001 and May 2006.

Main outcome measures: Mean daily BGL; independent effect of insulin regimen on mean daily BGL.

Results: Mean baseline BGL was not significantly different in patients receiving BBI and SSI (mean ± SD, 11.3 ± 4.1 v 10.6 ± 4.3 mmol/L; P = 0.23). After the first full day of therapy, mean daily BGL for patients receiving BBI was 1.6 ± 3.7 mmol/L lower than baseline BGL, and it remained 1.6-2.4 mmol/L lower than baseline throughout the study (P < 0.001). In contrast, there was no significant change in BGL for patients receiving SSI. Random effects regression analysis indicated that BBI was associated with a significantly lower mean daily BGL than SSI, independent of other variables (P < 0.001). The incidence of hypoglycaemia (BGL < 4 mmol/L) was significantly greater in patients receiving BBI than SSI (3.3% v 1.4%; P < 0.001), but there was no significant difference for severe hypoglycaemia (BGL < 2.8 mmol/L) (0.3 v 0.5%; P = 0.3).

Conclusions: Under routine clinical conditions, BBI is effective and safe across a range of patients and appears to be superior to SSI. Clinical improvements reflected those seen in a strict formal study setting.

Abstract
Objective: The associations between glucose intolerance measured at the study entry date and the 23-year incidence of coronary heart disease (CHD), CHD mortality, and total mortality were examined at the Honolulu Heart Program.

Research design and methods: This prospective study followed a cohort of 8,006 Japanese-American men who were 45-68 years old and living on the island of Oahu, HI, in 1965. Baseline glucose was measured in a nonfasting state 1 h after a 50-g glucose load. History and use of medication for diabetes was obtained during an interview. The cohort was divided into four categories of glucose tolerance: low-normal, high-normal, asymptomatic hyperglycemia, and known diabetes.

Results: During the 23 years of follow-up, 864 incident cases of CHD, 384 deaths from CHD, and 2,166 total deaths occurred. The relative risks (RRs) were obtained using Cox proportional hazards modeling, with the low-normal category as a reference. The RRs were adjusted for age only, as well as for age, BMI, hypertension, cholesterol, triglycerides, smoking, alcohol, and a Japanese diet index. The age-adjusted and risk factor-adjusted RRs for all outcomes were significant for the asymptomatic hyperglycemic and known diabetes groups (P<0.05). The age-adjusted RRs for CHD incidence and total mortality were marginally significant in the high-normal group, but the RRs were not significant when adjusted for risk factors.

Conclusions: These results suggest a dose-response relation of glucose intolerance at baseline with CHD incidence, CHD mortality, and total mortality, independent of other risk factors, in this cohort of middle-aged and older Japanese-American men.

Abstract
Admission hyperglycemia has been associated with increased hospital mortality in critically ill patients; however, it is not known whether hyperglycemia in patients admitted to general hospital wards is associated with poor outcome. The aim of this study was to determine the prevalence of in-hospital hyperglycemia and determine the survival and functional outcome of patients with hyperglycemia with and without a history of diabetes. We reviewed the medical records of 2030 consecutive adult patients admitted to Georgia Baptist Medical Center, a community teaching hospital in downtown Atlanta, GA, from July 1, 1998, to October 20, 1998. New hyperglycemia was defined as an admission or in-hospital fasting glucose level of 126 mg/dl (7 mmol/liter) or more or a random blood glucose level of 200 mg/dl (11.1 mmol/liter) or more on 2 or more determinations. Hyperglycemia was present in 38% of patients admitted to the hospital, of whom 26% had a known history of diabetes, and 12% had no history of diabetes before the admission. Newly discovered hyperglycemia was associated with higher in-hospital mortality rate (16%) compared with those patients with a prior history of diabetes (3%) and subjects with normoglycemia (1.7%; both P < 0.01). In addition, new hyperglycemic patients had a longer length of hospital stay, a higher admission rate to an intensive care unit, and were less likely to be discharged to home, frequently requiring transfer to a transitional care unit or nursing home facility. Our results indicate that in-hospital hyperglycemia is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without a history of diabetes. Patients with newly diagnosed hyperglycemia had a significantly higher mortality rate and a lower functional outcome than patients with a known history of diabetes or normoglycemia.

Abstract
Inpatient hyperglycemia in people with or without diabetes is associated with an increased risk of complications and mortality, a longer hospital stay, a higher admission rate to the intensive care unit, and higher hospitalization costs. Despite increasing evidence that supports intensive glycemic control in hospitalized patients, blood glucose control continues to be challenging, and sliding scale insulin coverage, a practice associated with limited therapeutic success, continues to be the most frequent insulin regimen in hospitalized patients. Sliding scale insulin has been in use for more than 80 years without much evidence to support its use as the standard of care. Several studies have revealed evidence of poor glycemic control and deleterious effects in sliding scale insulin use. To understand its wide use and acceptance, we reviewed the origin, advantages, and disadvantages of sliding scale insulin in the inpatient setting.

Abstract
Objective: The optimal treatment of hyperglycemia in general surgical patients with type 2 diabetes mellitus is not known.

Research design and methods: This randomized multicenter trial compared the safety and efficacy of a basal-bolus insulin regimen with glargine once daily and glulisine before meals (n = 104) to sliding scale regular insulin (SSI) four times daily (n = 107) in patients with type 2 diabetes mellitus undergoing general surgery. Outcomes included differences in daily blood glucose (BG) and a composite of postoperative complications including wound infection, pneumonia, bacteremia, and respiratory and acute renal failure.

Results: The mean daily glucose concentration after the 1st day of basal-bolus insulin and SSI was 145 ± 32 mg/dL and 172 ± 47 mg/dL, respectively (P < 0.01). Glucose readings <140 mg/dL were recorded in 55% of patients in basal-bolus and 31% in the SSI group (P < 0.001). There were reductions with basal-bolus as compared with SSI in the composite outcome [24.3 and 8.6%; odds ratio 3.39 (95% CI 1.50-7.65); P = 0.003]. Glucose <70 mg/dL was reported in 23.1% of patients in the basal-bolus group and 4.7% in the SSI group (P < 0.001), but there were no significant differences in the frequency of BG <40 mg/dL between groups (P = 0.057).

Conclusions: Basal-bolus treatment with glargine once daily plus glulisine before meals improved glycemic control and reduced hospital complications compared with SSI in general surgery patients. Our study indicates that a basal-bolus insulin regimen is preferred over SSI in the hospital management of general surgery patients with type 2 diabetes.

Abstract
Objective: We sought to study the optimal management of hyperglycemia in non-intensive care unit patients with type 2 diabetes, as few studies thus far have focused on the subject.

Research design and methods: We conducted a prospective, multicenter, randomized trial to compare the efficacy and safety of a basal-bolus insulin regimen with that of sliding-scale regular insulin (SSI) in patients with type 2 diabetes. A total of 130 insulin-naive patients were randomized to receive glargine and glulisine (n = 65) or a standard SSI protocol (n = 65). Glargine was given once daily and glulisine before meals at a starting dose of 0.4 units x kg(-1) x day(-1) for blood glucose 140-200 mg/dl or 0.5 units x kg(-1) x day(-1) for blood glucose 201-400 mg/dl. SSI was given four times per day for blood glucose >140 mg/dl.

Results: The mean admission blood glucose was 229 +/- 6 mg/dl and A1C 8.8 +/- 2%. A blood glucose target of <140 mg/dl was achieved in 66% of patients in the glargine and glulisine group and in 38% of those in the SSI group. The mean daily blood glucose between groups ranged from 23 to 58 mg/dl, with an overall blood glucose difference of 27 mg/dl (P < 0.01). Despite increasing insulin doses, 14% of patients treated with SSI remained with blood glucose >240 mg/dl. There were no differences in the rate of hypoglycemia or length of hospital stay.

Conclusions: Treatment with insulin glargine and glulisine resulted in significant improvement in glycemic control compared with that achieved with the use of SSI alone. Our study indicates that a basal-bolus insulin regimen is preferred over SSI in the management of non-critically ill, hospitalized patients with type 2 diabetes.

Abstract
Diabetes mellitus is now the most common cause of new cases of end-stage kidney disease treated with kidney replacement therapy in Australia. In addition to the approximately 5000 Australians receiving maintenance dialysis or living with a kidney transplant as a consequence of diabetes, many die from untreated end-stage kidney disease due to diabetes (DM-ESKD) each year. For every Australian receiving renal replacement therapy due to diabetes, at least 50 others have earlier stages of diabetic kidney disease (DKD). Based on projected increases in type 2 diabetes prevalence, the size of this underlying population with DKD will potentially exceed half a million by 2025. In addition to the risk of developing DM-ESKD, this population is at increased risk of premature cardiovascular morbidity and all-cause mortality. Higher rates of hospitalization, use of specialist services and prescription drugs mean that those with DKD also incur significantly greater health care costs compared with those with diabetes or chronic kidney disease alone. However, in contrast to the increasing prevalence of diabetes and early stages of DKD, recent trends in the incidence of DM-ESKD suggest that better management in the earlier stages of DKD has been successful in slowing rates of disease progression. Simultaneous improvements in use of renin-angiotensin inhibitors and improved glycaemic and blood pressure control are likely to be largely responsible for this trend. Primary prevention, maximizing early detection of DKD and optimal management of diabetes and kidney disease hold great potential to attenuate the future health burden attributable to DKD in Australia.

Abstract
Background: The objective of this study was to examine the association of Joint National Committee (JNC-V) blood pressure and National Cholesterol Education Program (NCEP) cholesterol categories with coronary heart disease (CHD) risk, to incorporate them into coronary prediction algorithms, and to compare the discrimination properties of this approach with other noncategorical prediction functions.

Methods and results: This work was designed as a prospective, single-center study in the setting of a community-based cohort. The patients were 2489 men and 2856 women 30 to 74 years old at baseline with 12 years of follow-up. During the 12 years of follow-up, a total of 383 men and 227 women developed CHD, which was significantly associated with categories of blood pressure, total cholesterol, LDL cholesterol, and HDL cholesterol (all P<.001). Sex-specific prediction equations were formulated to predict CHD risk according to age, diabetes, smoking, JNC-V blood pressure categories, and NCEP total cholesterol and LDL cholesterol categories. The accuracy of this categorical approach was found to be comparable to CHD prediction when the continuous variables themselves were used. After adjustment for other factors, approximately 28% of CHD events in men and 29% in women were attributable to blood pressure levels that exceeded high normal (> or =130/85). The corresponding multivariable-adjusted attributable risk percent associated with elevated total cholesterol (> or =200 mg/dL) was 27% in men and 34% in women.

Conclusions: Recommended guidelines of blood pressure, total cholesterol, and LDL cholesterol effectively predict CHD risk in a middle-aged white population sample. A simple coronary disease prediction algorithm was developed using categorical variables, which allows physicians to predict multivariate CHD risk in patients without overt CHD.

Abstract
Sliding-scale and basal-bolus insulin regimens are two options available for the treatment of severe or acute hyperglycemia in type 2 diabetes mellitus patients. Although its use is not recommended, sliding-scale insulin therapy is still being used widely. The aims of the study were to compare the glycemic control achieved by using sliding-scale or basal-bolus regimens for the management of severe or acute hyperglycemia in patients with type 2 diabetes and to analyze factors associated with the types of insulin therapy used in the management of severe or acute hyperglycemia. This retrospective study was conducted using the medical records of patients with acute or severe hyperglycemia admitted to a hospital in Malaysia from January 2008 to December 2012. A total of 202 patients and 247 admissions were included. Patients treated with the basal-bolus insulin regimen attained lower fasting blood glucose (10.8 ± 2.3 versus 11.6 ± 3.5 mmol/L; p = 0.028) and mean glucose levels throughout severe/acute hyperglycemia (12.3 ± 1.9 versus 12.8 ± 2.2; p = 0.021) compared with sliding-scale insulin regimens. Diabetic ketoacidosis (p = 0.043), cardiovascular diseases (p = 0.005), acute exacerbation of bronchial asthma (p = 0.010), and the use of corticosteroids (p = 0.037) and loop diuretics (p = 0.016) were significantly associated with the type of insulin regimen used. In conclusion, type 2 diabetes patients with severe and acute hyperglycemia achieved better glycemic control with the basal-bolus regimen than with sliding-scale insulin, and factors associated with the insulin regimen used could be identified.