Christopher A. Newton

Randomized Study of Basal-Bolus Insulin Therapy in the Inpatient Management of Patients With Type 2 Diabetes Undergoing General Surgery (RABBIT 2 Surgery)

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.

Comparison of Inpatient Insulin Regimens with Detemir plus Aspart Versus Neutral Protamine Hagedorn plus Regular in Medical Patients with Type 2 Diabetes

BACKGROUND Studies comparing the use of basal bolus with insulin analogs vs. split-mixed regimens with human insulins in hospitalized patients with type 2 diabetes are lacking. RESEARCH DESIGN AND METHODS In a controlled multicenter trial, we randomized 130 nonsurgical patients with blood glucose (BG) between 140 and 400 mg/dl to receive detemir once daily and aspart before meals (n = 67) or neutral protamine Hagedorn (NPH) and regular insulin twice daily (n = 63). Insulin dose was started at 0.4 U/kg.d for BG between 140 and 200 mg/dl or 0.5 U/kg.d for BG 201-400 mg/dl. Major study outcomes included differences in mean daily BG levels and frequency of hypoglycemic events between treatment groups. RESULTS Glycemic control improved similarly in both groups from a mean daily BG of 228 +/- 54 and 223 +/- 58 mg/dl (P = 0.61) to a mean daily BG level after the first day of 160 +/- 38 and 158 +/- 51 mg/dl in the detemir/aspart and NPH/regular insulin groups, respectively (P = 0.80). A BG target below 140 mg/dl before meals was achieved in 45% of patients in the detemir/aspart group and 48% in the NPH/regular group (P = 0.86). During treatment, 22 patients (32.8%) in the detemir/aspart group and 16 patients (25.4%) in the NPH/regular group had at least one episode of hypoglycemia (BG < 60 mg/dl) during the hospital stay (P = 0.34). CONCLUSIONS Treatment with basal/bolus regimen with detemir once daily and aspart before meals results in equivalent glycemic control and no differences in the frequency of hypoglycemia compared to a split-mixed regimen of NPH and regular insulin in patients with type 2 diabetes.

Randomized Study Comparing a Basal Bolus With a Basal Plus Correction Insulin Regimen for the Hospital Management of Medical and Surgical patients With Type 2 Diabetes: Basal Plus Trial

OBJECTIVE Effective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This multicenter trial randomized 375 patients with T2D treated with diet, oral antidiabetic agents, or low-dose insulin (≤0.4 units/kg/day) to receive a basal-bolus regimen with glargine once daily and glulisine before meals, a basal plus regimen with glargine once daily and supplemental doses of glulisine, and sliding scale regular insulin (SSI). RESULTS Improvement in mean daily blood glucose (BG) after the first day of therapy was similar between basal-bolus and basal plus groups (P = 0.16), and both regimens resulted in a lower mean daily BG than did SSI (P = 0.04). In addition, treatment with basal-bolus and basal plus regimens resulted in less treatment failure (defined as >2 consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL) than did treatment with SSI (0 vs. 2 vs. 19%, respectively; P < 0.001). A BG <70 mg/dL occurred in 16% of patients in the basal-bolus group, 13% in the basal plus group, and 3% in the SSI group (P = 0.02). There was no difference among the groups in the frequency of severe hypoglycemia (<40 mg/dL; P = 0.76). CONCLUSIONS The use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal-bolus regimen. The basal plus approach is an effective alternative to the use of a basal-bolus regimen in general medical and surgical patients with T2D.

Randomized Controlled Trial of Intensive Versus Conservative Glucose Control in Patients Undergoing Coronary Artery Bypass Graft Surgery: GLUCO-CABG Trial

OBJECTIVE The optimal level of glycemic control needed to improve outcomes in cardiac surgery patients remains controversial. RESEARCH DESIGN AND METHODS We randomized patients with diabetes (n = 152) and without diabetes (n = 150) with hyperglycemia to an intensive glucose target of 100–140 mg/dL (n = 151) or to a conservative target of 141–180 mg/dL (n = 151) after coronary artery bypass surgery (CABG) surgery. After the intensive care unit (ICU), patients received a single treatment regimen in the hospital and 90 days postdischarge. Primary outcome was differences in a composite of complications, including mortality, wound infection, pneumonia, bacteremia, respiratory failure, acute kidney injury, and major cardiovascular events. RESULTS Mean glucose in the ICU was 132 ± 14 mg/dL (interquartile range [IQR] 124–139) in the intensive and 154 ± 17 mg/dL (IQR 142–164) in the conservative group (P < 0.001). There were no significant differences in the composite of complications between intensive and conservative groups (42 vs. 52%, P = 0.08). We observed heterogeneity in treatment effect according to diabetes status, with no differences in complications among patients with diabetes treated with intensive or conservative regimens (49 vs. 48%, P = 0.87), but a significant lower rate of complications in patients without diabetes treated with intensive compared with conservative treatment regimen (34 vs. 55%, P = 0.008). CONCLUSIONS Intensive insulin therapy to target glucose of 100 and 140 mg/dL in the ICU did not significantly reduce perioperative complications compared with target glucose of 141 and 180 mg/dL after CABG surgery. Subgroup analysis showed a lower number of complications in patients without diabetes, but not in patients with diabetes treated with the intensive regimen. Large prospective randomized studies are needed to confirm these findings.

Safety and Efficacy of Sitagliptin Therapy for the Inpatient Management of General Medicine and Surgery Patients With Type 2 Diabetes: A pilot, randomized, controlled study

OBJECTIVE This study investigated the safety and efficacy of sitagliptin (Januvia) for the inpatient management of type 2 diabetes (T2D) in general medicine and surgery patients. RESEARCH DESIGN AND METHODS In this pilot, multicenter, open-label, randomized study, patients (n = 90) with a known history of T2D treated with diet, oral antidiabetic agents, or low total daily dose of insulin (≤0.4 units/kg/day) were randomized to receive sitagliptin alone or in combination with glargine insulin (glargine) or to a basal bolus insulin regimen (glargine and lispro) plus supplemental (correction) doses of lispro. Major study outcomes included differences in daily blood glucose (BG), frequency of treatment failures (defined as three or more consecutive BG >240 mg/dL or a mean daily BG >240 mg/dL), and hypoglycemia between groups. RESULTS Glycemic control improved similarly in all treatment groups. There were no differences in the mean daily BG after the 1st day of treatment (P = 0.23), number of readings within a BG target of 70 and 140 mg/dL (P = 0.53), number of BG readings >200 mg/dL (P = 0.23), and number of treatment failures (P > 0.99). The total daily insulin dose and number of insulin injections were significantly less in the sitagliptin groups compared with the basal bolus group (both P < 0.001). There were no differences in length of hospital stay (P = 0.78) or in the number of hypoglycemic events between groups (P = 0.86). CONCLUSIONS Results of this pilot indicate that treatment with sitagliptin alone or in combination with basal insulin is safe and effective for the management of hyperglycemia in general medicine and surgery patients with T2D.

A Comparison Study of Continuous Insulin Infusion Protocols in the Medical Intensive Care Unit: Computer-Guided Vs. Standard Column-Based Algorithms

PURPOSE To compare the safety and efficacy of continuous insulin infusion (CII) via a computer-guided and a standard paper form protocol in a medical intensive care unit (ICU). METHODS Multicenter randomized trial of 153 ICU patients randomized to CII using the Glucommander (n = 77) or a standard paper protocol (n = 76). Both protocols used glulisine insulin and targeted blood glucose (BG) between 80 mg/dL and 120 mg/dL. RESULTS The Glucommander resulted in a lower mean BG value (103 ± 8.8 mg/dL vs. 117 ± 16.5 mg/dL, P < 0.001) and in a shorter time to reach BG target (4.8 ± 2.8 vs.7.8 hours ± 9.1 hours, P < 0.01), and once at target resulted in a higher percentage of BG readings within target (71.0 ± 17.0% vs. 51.3 ± 19.7%, P < 0.001) than the standard protocol. Mean insulin infusion rate in the Glucommander was similar to the standard protocol (P = 0.12). The percentages of patients with ≥1 episode of BG <40 mg/dL and <60 mg/dL were 3.9% and 42.9% in the Glucommander and 5.6% and 31.9% in the standard, respectively [P = not significant (NS)]. Repeated measures analyses show that the probabilities of BG reading <40 mg/dL or <60 mg/dL were not significantly different between groups (P = 0.969, P = 0.084) after accounting for within-patient correlations with or without adjusting for time effect. There were no differences between groups in the length of hospital stay (P = 0.704), ICU stay (P = 0.145), or inhospital mortality (P = 0.561). CONCLUSION Both treatment algorithms resulted in significant improvement in glycemic control in critically ill patients in the medical ICU. The computer-based algorithm resulted in tighter glycemic control without an increased risk of hypoglycemic events compared to the standard paper protocol.

Risk factors for inpatient hypoglycemia during subcutaneous insulin therapy in non-critically ill patients with type 2 diabetes.

Objective: We aimed to determine risk factors associated with hypoglycemia during subcutaneous insulin therapy in non-critically ill patients with type 2 diabetes. Methods: We conducted an analysis of three randomized control trials using basal/bolus regimen and regular sliding scale insulin (SSI) in patients with diabetes admitted to medical and surgical settings. Results: We analyzed medical records of 261 general medicine and 211 noncardiac surgery patients treated with basal/ bolus regimen with glargine/glulisine (n = 169), detemir/aspart (n = 67), neutral protamine Hagedorn/regular (n = 63), or with SSI (n = 173). The overall frequency of mild and severe hypoglycemia (<70 and <40 mg/dl) was 19% and 2%, respectively. During treatment, medical patients experienced a higher number of hypoglycemia than surgical patients (23% versus 13%; p = .005), but the rate of severe hypoglycemia was similar between groups (1.9% versus 1.9%; p = not significant). Increasing age, impaired kidney function (glomerular filtration rate < 60 ml/min), total daily insulin dose, and type of insulin regimen (basal/bolus versus SSI) during hospitalization were important contributors for hypoglycemia in both medical and surgical patients. Among these variables, increasing age and type of insulin regimen (basal/bolus versus SSI) were found to be independent predictors of hypoglycemic events. Conclusions: Mild hypoglycemic events are common during subcutaneous insulin therapy in medical and surgical patients with type 2 diabetes. Increasing age, impaired renal function, daily insulin dose, and insulin regimen (basal/bolus versus SSI) are important predictors of hypoglycemia during insulin therapy in patients with type 2 diabetes mellitus.

Substitution of Standard Soybean Oil with Olive Oil-Based Lipid Emulsion in Parenteral Nutrition: Comparison of Vascular, Metabolic, and Inflammatory Effects

CONTEXT Soybean oil-based lipid emulsions are the only Food and Drug Administration-approved lipid formulation for clinical use in parenteral nutrition (PN). Recently concerns with its use have been raised due to the proinflammatory effects that may lead to increased complications because they are rich in ω-6 polyunsaturated fatty acids. METHODS This was a prospective, randomized, controlled, crossover study comparing the vascular, metabolic, immune, and inflammatory effects of 24-h infusion of PN containing soybean oil-based lipid emulsion (Intralipid), olive oil-based (ClinOleic), lipid free, and normal saline in 12 healthy subjects. RESULTS Soybean oil-PN increased systolic blood pressure compared with olive oil-PN (P < 0.05). Soybean oil PN reduced brachial artery flow-mediated dilatation from baseline (-23% at 4 h and -25% at 24 h, both P < 0.01); in contrast, olive oil PN, lipid free PN, and saline did not change either systolic blood pressure or flow-mediated dilatation. Compared with saline, soybean oil PN, olive oil PN, and lipid free PN similarly increased glucose and insulin concentrations during infusion (P < 0.05). There were no significant changes in plasma free fatty acids, lipid profile, inflammatory and oxidative stress markers, immune function parameters, or sympathetic activity between soybean oil- and olive oil-based lipid emulsions. CONCLUSION The 24-h infusion of PN containing soybean oil-based lipid emulsion increased blood pressure and impaired endothelial function compared with PN containing olive oil-based lipid emulsion and lipid-free PN in healthy subjects. These vascular changes may have significant implications in worsening outcome in subjects receiving nutrition support. Randomized controlled trials with relevant clinical outcome measures are needed in patients receiving PN with olive oil-based and soybean oil-based lipid emulsions.

Hospital Discharge Algorithm Based on Admission HbA1c for the Management of Patients With Type 2 Diabetes

OBJECTIVE Effective treatment algorithms are needed to guide diabetes care at hospital discharge in general medicine and surgery patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This was a prospective, multicenter open-label study aimed to determine the safety and efficacy of a hospital discharge algorithm based on admission HbA1c. Patients with HbA1c <7% (53.0 mmol/mol) were discharged on their preadmission diabetes therapy, HbA1c between 7 and 9% (53.0–74.9 mmol/mol) were discharged on a preadmission regimen plus glargine at 50% of hospital daily dose, and HbA1c >9% were discharged on oral antidiabetes agents (OADs) plus glargine or basal bolus regimen at 80% of inpatient dose. The primary outcome was HbA1c concentration at 12 weeks after hospital discharge. RESULTS A total of 224 patients were discharged on OAD (36%), combination of OAD and glargine (27%), basal bolus (24%), glargine alone (9%), and diet (4%). The admission HbA1c was 8.7 ± 2.5% (71.6 mmol/mol) and decreased to 7.3 ± 1.5% (56 mmol/mol) at 12 weeks of follow-up (P < 0.001). The change of HbA1c from baseline at 12 weeks after discharge was −0.1 ± 0.6, −0.8 ± 1.0, and −3.2 ± 2.4 in patients with HbA1c <7%, 7–9%, and >9%, respectively (P < 0.001). Hypoglycemia (<70 mg/dL) was reported in 22% of patients discharged on OAD only, 30% on OAD plus glargine, 44% on basal bolus, and 25% on glargine alone and was similar in patients with admission HbA1c ≤7% (26%) compared with those with HbA1c >7% (31%, P = 0.54). CONCLUSIONS Measurement of HbA1c on admission is beneficial in tailoring treatment regimens at discharge in general medicine and surgery patients with type 2 diabetes.

Impairments in site-specific AS160 phosphorylation and effects of exercise training

The purpose of this study was to determine if site-specific phosphorylation at the level of Akt substrate of 160 kDa (AS160) is altered in skeletal muscle from sedentary humans across a wide range of the adult life span (18–84 years of age) and if endurance- and/or strength-oriented exercise training could rescue decrements in insulin action and skeletal muscle AS160 phosphorylation. A euglycemic-hyperinsulinemic clamp and skeletal muscle biopsies were performed in 73 individuals encompassing a wide age range (18–84 years of age), and insulin-stimulated AS160 phosphorylation was determined. Decrements in whole-body insulin action were associated with impairments in insulin-induced phosphorylation of skeletal muscle AS160 on sites Ser-588, Thr-642, Ser-666, and phospho-Akt substrate, but not Ser-318 or Ser-751. Twelve weeks of endurance- or strength-oriented exercise training increased whole-body insulin action and reversed impairments in AS160 phosphorylation evident in insulin-resistant aged individuals. These findings suggest that a dampening of insulin-induced phosphorylation of AS160 on specific sites in skeletal muscle contributes to the insulin resistance evident in a sedentary aging population and that exercise training is an effective intervention for treating these impairments.