Improved Safety and Efficacy of Small-Bore Feeding Tube Confirmation Using an Electromagnetic Placement Device.

BACKGROUND: Early enteral nutrition has been shown to decrease complications and improve patient outcomes. Post pyloric feeding is recommended for patients with gastric intolerance or at high risk for aspiration. Feeding tube placement can be challenging and pose risk of pulmonary complications. Reliance on radiographic confirmation for feeding tube placement exposes the patient to radiation. Electromagnetic placement device (EMPD) may offer a method to minimize pulmonary complications, increase successful placement, and decrease radiation exposure to the patient. OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of using EMPD verification, instead of routine abdominal radiographic confirmation, for small-bore feeding tube placement. RESULTS: Variables evaluated were adverse events, utilization of radiographs for confirmation, and success rate of feeding tube placement in the ordered location. Two time frames were reviewed. In a 1-year period, 3754 small-bore feeding tubes were placed using EMPD, with zero adverse events noted. Radiographic confirmation was utilized in 0%-29.2% of the EMPD placed tubes. Successful placement of feeding tubes using EMPD ranged from 94%-99.6%. During a 5-year period, 7081 EMPD feeding tubes were evaluated. One adverse event, pneumothorax, occurred during the placement of these 7081 tubes, for a rate of 0.014%. CONCLUSION: Feeding tube placement confirmation is safe and efficacious via EMPD providing an effective method of feeding tube placement with a success rate >94% into the desired location. EMPD is an accurate verification method of distal tip location, eliminating the need for routine abdominal radiographic confirmation.

Recommendations for Systematic Statistical Computation of Immunogenicity Cut Points.

Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti-drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three-tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme. Depending on a biotherapeutic's structural attributes, more characterization and testing may be appropriate. Unlike bioanalytical assays used to support the evaluation of pharmacokinetics or toxicokinetics, an important component in immunogenicity testing is the calculation of cut points for the identification (screening), confirmation (specificity), and titer assessment responses in animals and humans. Several key publications have laid an excellent foundation for statistical design and data analysis to determine immunogenicity cut points. Yet, the process for statistical determination of cut points remains a topic of active discussion by investigators who conduct immunogenicity assessments to support biotherapeutic drug development. In recent years, we have refined our statistical approach to address the challenges that have arisen due to the evolution in biotherapeutics and the analytical technologies used for quasi-quantitative detection. Based on this collective experience, we offer a simplified statistical analysis process and flow-scheme for cut point evaluations that should work in a large majority of projects to provide reliable estimates for the screening, confirmatory, and titering cut points.

Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus.

Glucagon-like peptide-1 receptor agonists, used to treat type 2 diabetes mellitus, are associated with small reductions in systolic blood pressure (SBP) and increases in heart rate. However, findings based on clinic measurements do not adequately assess a drug's 24-hour pharmacodynamic profile. The effects of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, on BP and heart rate were investigated using ambulatory BP monitoring. Patients (n=755; 56±10 years; 81% white; 48% women), with type 2 diabetes mellitus, taking ≥1 oral antihyperglycemic medication, with a clinic BP between 90/60 and 140/90 mm Hg were randomized to dulaglutide (1.5 or 0.75 mg) or placebo subcutaneously for 26 weeks. Ambulatory BP monitoring was performed at baseline and at 4, 16, and 26 weeks. The primary end point was change from baseline to week 16 in mean 24-hour SBP, a tree gatekeeping strategy compared the effects of dulaglutide to placebo. Both doses of dulaglutide were noninferior to placebo for changes in 24-hour SBP and diastolic blood pressure, and dulaglutide 1.5 mg significantly reduced SBP (least squares mean difference [95% confidence interval]), -2.8 mm Hg [-4.6, -1.0]; P≤0.001). Dulaglutide 0.75 mg was noninferior to placebo (1.6 bpm; [0.3, 2.9]; P≤0.02) for 24-hour heart rate (least squares mean difference [95% confidence interval]), but dulaglutide 1.5 mg was not (2.8 bpm [1.5, 4.2]). Dulaglutide 1.5 mg was associated with a reduction in 24-hour SBP and an increase in 24-hour heart rate. The mechanisms responsible for the observed effects remain to be clarified.

A 16-week open-label, multicenter pilot study assessing insulin pump therapy in patients with type 2 diabetes suboptimally controlled with multiple daily injections.

BACKGROUND: We assessed the efficacy, safety, and patient-reported outcomes (PROs) of insulin pump therapy in patients with type 2 diabetes mellitus (T2DM) who were suboptimally controlled with a multiple daily injection (MDI) regimen. METHODS: In this subanalysis of a 16-week multicenter study, 21 insulin-pump-naïve patients [age 57 ± 13 years, hemoglobin A1c (A1C) 8.4 ± 1.0%, body weight 98 ± 20 kg, total daily insulin dose 99 ± 65 U, mean ± standard deviation] treated at baseline with MDI therapy with or without oral antidiabetic agents discontinued all diabetes medications except metformin and initiated insulin pump therapy. Insulin was titrated to achieve the best possible glycemic control with the simplest possible dosing regimen. Outcome measures included A1C, fasting and postprandial glucose, body weight, incidence of hypoglycemia, and PROs. RESULTS: Glycemic control improved significantly after 16 weeks: A1C 7.3 ± 1.0% (-1.1 ± 1.2%, p < .001), fasting glucose 133 ± 33 mg/dl (-32 ± 74 mg/dl, p < .005), and postprandial glucose 153 ± 35 mg/dl (-38 ± 46 mg/dl, p < .001). At week 16, the mean daily basal, bolus, and total insulin doses were 66 ± 36, 56 ± 40, and 122 ± 72 U (1.2 U/kg), respectively, and 90% of patients were treated with two or fewer daily basal rates. Body weight increased by 2.8 ± 2.6 kg (p < .001). Mild hypoglycemia was experienced by 81% of patients at least once during the course of the study with no episodes of severe hypoglycemia. There were significant improvements in PRO measures. CONCLUSIONS: Insulin pump therapy using a relatively simple dosing regimen safely improved glucose control and PROs in patients with T2DM who were unable to achieve glycemic targets with MDI therapy. Controlled trials are needed to further assess the clinical benefits and cost-effectiveness of insulin pumps in this patient population.

Comparison of a novel insulin bolus-patch with pen/syringe injection to deliver mealtime insulin for efficacy, preference, and quality of life in adults with diabetes: a randomized, crossover, multicenter study.

OBJECTIVE: This study compared the efficacy, safety, device satisfaction, and quality of life (QOL) in people with diabetes using an insulin bolus-patch versus current devices (pen/syringe) to deliver mealtime insulin. RESEARCH DESIGN AND METHODS: Thirty-eight subjects with diabetes (26 with type 1 and 12 with type 2) were randomized to bolus-patch or current injection device (55% pen and 45% syringe) to deliver mealtime insulin in a multicenter, 6-week crossover study. Efficacy was assessed by equivalence in mean daily seven-point blood glucose (MDBG). Safety assessments included severe hypoglycemia episodes, adverse device effects (ADEs), and adverse events (AEs). Device satisfaction was determined by the validated Insulin Delivery System Rating Questionnaire (IDSRQ) and QOL by the validated Diabetes Specific QOL Scale (DSQOLS). RESULTS: Using bolus-patch, MDBG (mean±SE) was equivalent to that using pen/syringe (8.61±0.28 vs. 9.02±0.26 mmol/L; P=0.098). SD of the seven-point blood glucose measurements was lower using bolus-patch (3.18±0.18 vs. 3.63±0.17 mmol/L; P=0.004), as was the coefficient of variation (CV) (37.2±1.7 vs. 40.3±1.7%; P=0.046). Hemoglobin A1c, 1,5-anhydroglucitol, fructosamine, and insulin use were similar between groups. There were no severe hypoglycemia episodes or serious ADEs. Between-device AEs were comparable. Subjects scored better on six of seven subscales on the DSQOLS and five of six subscales on the IDSRQ while using bolus-patch versus pen/syringe. At study completion, 76% of subjects would choose to switch to bolus-patch (P=0.001). CONCLUSIONS: Delivery of mealtime insulin with bolus-patch compared with pen/syringe resulted in equivalent MDBG, lower SD and CV of seven-point blood glucose measurements, good safety, significant device satisfaction, and improved QOL.

Insulin pump therapy in patients with type 2 diabetes safely improved glycemic control using a simple insulin dosing regimen.

BACKGROUND: This study assessed insulin dose and dosing patterns required to optimize glycemic control with an insulin pump in patients with type 2 diabetes. METHODS: In this 16-week, open-label, multicenter, pilot study, 56 insulin pump-naive patients treated at baseline with two or more oral antidiabetes agents (OADs), basal insulin with or without OADs, or basal-bolus insulin with or without OADs discontinued all diabetes medications except metformin and initiated insulin pump therapy. Insulin doses were adjusted to optimize glycemic control with the simplest possible insulin regimen. Outcomes included total daily insulin dose, daily basal and bolus insulin doses, number of daily basal rates, hemoglobin A1C, fasting and postprandial glucose, patient-reported outcomes and rate of hypoglycemia. RESULTS: After 16 weeks of pump therapy, the mean +/- SD total daily insulin dose was 95 +/- 59 U. The percentage of the total daily insulin dose used as basal and as bolus delivery was 55% and 45%, respectively. Eighty-eight percent of patients were treated with two or fewer daily basal rates. Mean A1C was lowered by 1.2 +/- 1.2% (P < 0.001), and there was no severe hypoglycemia. Mean change in body weight was +1.9 +/- 3.3 kg (P < 0.001). Overall treatment preference improved with pump therapy compared to baseline. CONCLUSIONS: Insulin pump therapy using a simple dosing regimen significantly improved glycemic control in patients with type 2 diabetes. Patients experienced limited weight gain, there was no severe hypoglycemia, and overall treatment preference improved significantly.

Exenatide added to insulin therapy: a retrospective review of clinical practice over two years in an academic endocrinology outpatient setting.

BACKGROUND: Exenatide is an antidiabctic agent currently indicated as adjunctive therapy with oral agents for the treatment of type 2 diabetes mellitus (T2DM). Limited published data exist on the off-label use of exenatide in conjunction with insulin in the treatment of T2DM. OBJECTIVE: The aim of this retrospective study was to examine the effects of exenatide on glycemic control, weight, and insulin dose in patients with T2DM treated with insulin. METHODS: Patients with T2DM receivirg insulin and adjuvant therapy with exenatide at an endocrinology clinic at a university hospital for up to 27 months were eligible for inclusion. Glycosylated hemoglobin (HbA(1c)), weight, insulin doses (total, prandial, and basal), concurrent oral antidiabetic medications, and adverse events were ascertained by retrospective review of medical records and were considered the clinical parameters of interest. The last observation in 4 specified time intervals (0-6, 6-12, 12-18, and 18-27 months) for each clinical parameter was used in the analysis. RESULTS: Of the 3397 patients with a confirmed diagnosis of T2DM who were seen at the clinic during the study period, 268 patients met inclusion criteria and were enrolled in the study. Of the 268 patients enrolled, 38 discontinued therapy within the first 2 months, 30 were lost to follow-up, and 12 did not have evaluable data. These latter patients without sufficient data (n = 42) were not included in the primary analysis but were included in the adverse events analysis. Overall, data from 188 patients (mean [SD] age, 56 (9) years; 85 [45%] men; body mass index, 40.4 [8.4] kg/m(2); 160 [85%] white) were evaluated (mean duration of treatment, 350 [208] days) and included in all analyses. The mean baseline values for HbA(1c), weight, and total daily insulin dose before exenatide therapy were 8.05% (1.47%), 117.8 (24.7) kg, and 99.9 (90.0) U, respectively. For the 4 time intervals, the mean changes in HbA(1c) were: -0.66% (1.54%) at 0 to 6 months (P < 0.001); -0.55% (1.4%) at 6 to 12 months (P < 0.001); -0.54% (1.83%) at 12 to 18 months (P = 0.019); and -0.54% (1.37%) at 18 to 27 months (P = 0.020). Mean weight significantly declined with increasing treatment duration. Mean changes in weight were: -2.4 (5.1) kg at 0 to 6 months (P < 0.001); -4.3 (7.2) kg at 6 to 12 months (P < 0.001); -6.2 (9.7) kg at 12 to 18 months (P < 0.001); and -5.5 (10.8) kg at 18 to 27 months (P < 0.01). After 18 months, an increase in weight was observed; but the increase remained lower than baseline. The mean insulin total daily dose (TDD) was decreased in all patients at the 0- to 6-month (-18.0 [49.9] U; P < 0.001) and the 6- to 12-month (-14.8 [35.3] U; P < 0.001) intervals. Mean changes in insulin TDD during the 12- to 18-month and 18- to 27-month intervals were not statistically significant. The mean percent change from baseline in the basal insulin dose at 0 to 6 months, 6 to 12 months, 12 to 18 months, and 18 to 27 months was not statistically significant. For the 4 intervals, the mean percent change from baseline in the prandial insulin dose was -33.5% (56.2%) at 0 to 6 months (P < 0.001); -25.9% (59.7%) at 6 to 12 months (P = 0.002); -29.7% (74.8%) at 12 to 18 months (P = 0.02); and -55.7% (56.8%) at 18 to 27 months (P = 0.005). Of the 226 patients who were treated with exenatide + insulin for any length of time (including within the first 2 months), 59 (26.1%) discontinued exenatide because of adverse events. The adverse events were largely considered mild and included nausea (n = 51 [22.6% of patients]), vomiting (22 [9.7%]), hypoglycemia (9 [4.0%]), heartburn (2 [0.9%]), diarrhea (1 [0.4%]), constipation (1 [0.4%]), malaise (1 [0.4%]), and generalized edema (1 [0.4%]). Two serious adverse events occurred during the study period: acute renal failure not attributed to exenatide (1 [0.4%]); and pancreatitis (1 [0.4%]), both of which required hospitalization 1 month after the start of exenatide therapy. CONCLUSION: In this retrospective review of patients with T2DM treated in an outpatient setting, the addition of exenatide to insulin-based therapy was associated with reductions in mean HbA(1c), weight, and prandial insulin requirements for treatment periods of up to 27 months, and in total insulin requirements for treatment periods of up to 12 months.

Relating glucose clamp profiles to reduction of blood glucose after insulin administration.

A model was established allowing prediction of blood glucose response from glucose clamp results performed in healthy volunteers. Data from published studies performed in healthy volunteers were used to establish, test, and validate a model for the evaluation of glucose reductions from glucose clamp results. Studies included those that measured blood glucose and glucodynamic response over time after administration of 0.05 U/kg of regular human insulin (HR) and insulin lispro (LP) with and without the benefit of a glucose clamp procedure. An inhibitory effect E(max) model was used to describe the relationship; the model differed between the HR and LP responses by the intensity of the counterregulatory response as assessed by glucagon measurements. The relationships were used to predict blood glucose responses from a clamp study assessing NPH insulin and HR administrations. Glucose concentrations measured after administration of NPH insulin and HR without a clamp were compared to the model-predicted results to assess the accuracy of the model predictions. The E(max) model successfully correlated the glucose clamp results with the blood glucose depressions in the presence and absence of a counterregulatory response. However, predictions of glucose depression were only accurately modeled in the absence of a counterregulatory glucagon response. The correlations established with a minimal counterregulatory response underscore the value of glucose clamp procedures in defining the time-activity profiles of insulins when the clamp is established at fasting glucose concentrations.

Effect of long-term exposure to insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes.

OBJECTIVE: To determine the long-term effects of insulin lispro on inducing lispro-specific, insulin-specific, and cross-reactive (reactive with both insulin lispro and human insulin) antibodies. RESEARCH DESIGN AND METHODS: A multinational, multicenter combination of controlled and noncontrolled, open-label studies of 4.5 years' duration was designed to evaluate the long-term immunologic profile of subcutaneously administered insulin lispro. A total of 1,221 patients (men and women; 12-81 years of age) with type 1 or type 2 diabetes were enrolled. Circulating anti-insulin antibodies were measured using radioimmunoassays. RESULTS: Insulin-specific and lispro-specific antibody responses were within the background noise levels of the assays. Significant elevations of antibody were confined to a cross-reactive antibody response. Antibody levels resulting from prior exposure to long- and short-acting insulins changed little after transfer to insulin lispro and remained within or near the baseline levels. De novo exposure to insulin lispro resulted in increases in cross-reactive but not insulin- or lispro-specific antibody levels. Cross-reactive insulin antibodies developed more readily in patients with type 1 diabetes than in those with type 2 diabetes. Long-term antibody responses tended to decrease over time and returned to baseline or near-baseline levels by the end of the long-term studies. No evidence of an anamnestic antibody response could be found in individuals treated intermittently with insulin lispro. CONCLUSIONS: The immunogenic profile of patients treated with insulin lispro was comparable to that of patients treated with recombinant human insulin. Inductions of significant levels of specific or cross-reactive antibodies were not observed in patients who had received insulin previously. No significant antibody-dependent increases in insulin dosage requirements were noted in these patients. The incidence of insulin allergy was not different from that in patients treated with recombinant regular human insulin.