Effect of Total Daily Dose on Efficacy,Dosing, and Safety of 2 Dose Titration Regimens of Human Regular U-500 Insulin in Severely Insulin-Resistant Patients with Type 2 Diabetes

Objective: To examine the influence of baseline U-100 insulin total daily dose (TDD) on clinical outcomes in severely insulin-resistant patients with inadequately controlled type 2 diabetes treated with human regular U-500 insulin (U-500R) from the perspective of current dosing recommendations.Methods: Data from a recent prospective, randomized trial comparing thrice-daily (TID) and twice-daily (BID) U-500R in 325 patients transitioned from highdose/high-volume U-100 insulin were analyzed across baseline U-100 TDD units and units/kg subgroups (≤300 units [n = 224, 68.9%] and >300 units [n = 101, 31.1%]; ≤2 units/kg [n = 96, 29.5%] and >2 units/kg [n = 229, 70.5%]). Subgroup effects on treatment differences were evaluated, and outcomes between treatment-pooled subgroups were compared.Results: At 24 weeks, significant reductions in glycated hemoglobin (HbA1c) were observed for all subgroups (range: -1.01% to -1.38%, P<.05). Within-subgroup treatment effects were similar with no treatment-by-subgroup interactions; however, a greater reduction was noted in the >300-units subgroup (P = .04). No TID/BID differences within subgroups or treatment-by-subgroup interactions were observed for TDD or weight increase from baseline. Overall hypoglycemia rates were similar between treatments (within subgroups) and showed no interactions. However, rates were higher in the >300-units subgroup for severe hypoglycemia (P = .04) and in both higher-dose subgroups for documented symptomatic hypoglycemia ≤70 mg/dL (P<.001, units; P = .001, units/kg).Conclusion: Both TID and BID U-500R were efficacious and safe across TDD subgroups, though higher hypoglycemia rates were observed in higher-dose, treatment-pooled subgroups. U-500R dosing recommendations have been updated accordingly.Abbreviations:AE = adverse eventBID = twice dailyHbA1c = glycated hemoglobinQID = 4 times dailyRCT = randomized clinical trialT2D = type 2 diabetesTDD = total daily doseTID = thrice dailyU-500R = human regular U-500 insulin     

Glycemic Outcomes of Hospitalized Patients on Ambulatory Humulin-R U-500 Insulin

ObjectiveManaging hospitalized patients on ambulatory U-500 insulin is challenging because of limited guidance on how to safely adjust insulin doses during admission. We sought to evaluate glycemic outcomes in relation to inpatient insulin doses in patients receiving U-500 prior to hospitalization.MethodsRetrospective study of hospitalized patients on ambulatory U-500 seen consecutively from January 2015 to December 2019. Primary outcomes were inpatient hypoglycemia, hyperglycemia, and normoglycemia at different insulin dosages expressed as weight-based (unit/kg/d) inpatient total daily dose (TDD) and ratio of inpatient to outpatient TDD.ResultsWe identified 66 admissions of 46 unique patients. The median (interquartile range) body mass index was 41.0 kg/m² (35.1, 46.8), home TDD 212 units (120, 300), and home insulin dose 1.6 units/kg/d (1.1, 2.2). The median (interquartile range) inpatient insulin dose was 0.7 unit/kg/d (0.3, 1.0) and the ratio of inpatient to outpatient TDD was 0.4 (0.2, 0.8). Hyperglycemia persisted throughout the hospitalization. For the outcomes of hyperglycemia and normoglycemia, we found no association between increased levels of insulin dosages. For the outcome of hypoglycemia, significantly higher odds were observed when non-fasting patients received an inpatient TDD that was either > 40% of their home TDD or > 0.6 unit/kg/d of insulin.ConclusionPatients on ambulatory U-500 have significant hyperglycemia during admission. Inpatient insulin doses of 40% of home TDD or ≤ 0.6 unit/kg were not associated with increased hypoglycemia risk. Further prospective studies are needed to determine effective doses in these high-risk patients.     

Two Treatment Approaches for Human Regular U-500 Insulin in Patients With Type 2 Diabetes not Achieving Adequate Glycemic Control on High-Dose U-100 Insulin Therapy With or Without Oral Agents: A Randomized,Titration-To-Target Clinical Trial

Objective: To compare the efficacy and safety of 2 dosing regimens for human regular U-500 insulin (U-500R, 500 units/mL) replacing high-dose U-100 insulins with or without oral antihyperglycemic drugs in patients with inadequately controlled type 2 diabetes (T2D).Methods: We conducted a 24-week, open-label, parallel trial in 325 patients (demographics [means]: age, 55.4 years; diabetes duration, 15.2 years; body mass index, 41.9 kg/m²; glycated hemoglobin [HbA_1c], 8.7%; U-100 insulin dose, 287.5 units administered in 5 injections/day [median; range, 2 to 10]). Patients were randomized to thrice-daily (TID, n = 162) or twice-daily (BID, n = 163) U-500R after a 4-week lead-in period. The primary outcome was HbA_1c change from baseline.Results: After 24 weeks, both treatments demonstrated significant HbA_1c reductions (TID, -1.12%; BID, -1.22%; both, P<.001) and clinical equivalence (difference, -0.10%; 95% confidence interval, -0.33 to 0.12%; noninferiority margin, 0.4%). Comparable increases in total daily U-500R dose (TID, 242.7 to 343.1 units; BID, 249.0 to 335.0 units) were observed. Incidence and rate of documented symptomatic hypoglycemia (≤70 mg/dL) were lower for TID versus BID (P = .003 and P = .02, respectively); severe hypoglycemia was similar between treatments. Weight gain was similar in both groups (TID, 5.4 kg; BID, 4.9 kg).Conclusion: Initiation and titration of U-500R using either algorithm (TID or BID) improves glycemic control effectively and safely with fewer injections in patients with T2D treated with high-dose/high-volume U-100 insulin. These results provide clinicians with a practical framework for using U-500R in severely insulin-resistant patients with suboptimally controlled T2D.Abbreviations: BID = twice daily FAS = full analysis set HbA_1c = glycated hemoglobin PG = plasma glucose SMPG = self-monitored plasma glucose T2D = type 2 diabetes TDD = total daily dose TID = thrice daily U-500R = human regular U-500 insulin     

Optimized Human Regular U-500 Insulin Treatment Improves β-Cell Function in Severely Insulin-Resistant Patients with Long-Standing Type 2 Diabetes and High Insulin Requirements

Objective: To assess β-cell function and insulin sensitivity following improvement in glycemic control in severely insulin-resistant patients with poorly controlled type 2 diabetes (T2D).Methods: A subset of patients in a 24-week, open-label, randomized trial comparing thrice-daily (n = 14/162) versus twice-daily (n = 11/163) human regular U-500 insulin (U-500R) underwent mixed meal tolerance testing at baseline and endpoint. Baseline characteristics were similar between treatment groups (combined means: age, 54.0 years; diabetes duration, 13.6 years; body mass index, 38.8 kg/m²; glycated hemoglobin &lsqb;HbA_1c], 8.3%; U-100 insulin dose, 287.6 units/day, 2.6 units/kg/day). Primary outcome measure was ratio of area under the curve (AUC) for C-peptide to glucose (AUC_C-peptide/AUC_glucose) at 24-week endpoint.Results: Change from baseline HbA_1c, daily U-500R dose, and weight were -1.17% (P = .0002), +80.8 units (P = .0003), and +5.9 kg (P = .33), respectively. β-Cell function significantly improved after 24 weeks of U-500R therapy in combined treatment groups. The AUC_C-peptide/AUC_glucose increased 34.0% (ratio of least-squares geometric mean, 1.34; 95% confidence interval, 1.18 to 1.52; P = .0001). Integral of total insulin secretion rate increased from 27.0 to 33.7 nmol/m², and glucose sensitivity improved from 18.3 to 24.0 pmol/min/m²/mM (both, P = .02). Matsuda index improved from 0.8 to 1.3 (P = .008).Conclusion: Despite long-standing diabetes and poor glycemic control at baseline, functional recovery of β-cells was observed with improved glycemic control in these severely insulin-resistant patients with T2D, possibly due to alleviation of glucotoxicity.Abbreviations:AUC = area under the curveBID = twice dailyHbA_1c = glycated hemoglobinISR = insulin secretion rateLSM = least-squares meanMMTT = mixed meal tolerance testPG = plasma glucoseT2D = type 2 diabetesTDD = total daily doseTID = thrice dailyU-500R = human regular U-500 insulin     

Reduced Hypoglycemia and Comparable Efficacy with Insulin Glargine 300 U/ML Versus Insulin Glargine 100 U/ML in Patients with Type 2 Diabetes Achieving Different Levels of Prebreakfast Self-Monitored Plasma Glucose

Objective: To evaluate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) and insulin glargine 100 U/mL (Gla-100) in patients with type 2 diabetes (T2D) who reached prebreakfast self-monitored plasma glucose (SMPG) levels <100 and <130 mg/dL.Methods: This was a post hoc analysis of insulin-naïve (EDITION 3, NCT01676220) and experienced (EDITION 2, NCT01499095) patients with uncontrolled T2D, randomized to 6 months of Gla-300 versus Gla-100 treatment. Endpoints included glycated hemoglobin A1c change, hypoglycemia incidence, and event rates. Separate comparisons were done for patients achieving prebreak-fast fasting glucose of <100 versus ≥100 mg/dL and <130 versus ≥130 mg/dL.Results: Efficacy did not differ significantly between treatments in either study. Overall, basal insulin doses were ~10% higher with Gla-300 versus Gla-100. EDITION 2: overall and documented (≤70 mg/dL) hypoglycemia rates were significantly lower with Gla-300 versus Gla-100 in all SMPG groups except <100 mg/dL; nocturnal hypoglycemia rates were significantly lower with Gla-300 in all SMPG groups. EDITION 3: overall hypoglycemia rates were significantly lower with Gla-300 in patients with SMPG ≥100 mg/dL and those with SMPG <130 mg/dL; documented hypoglycemia rates were significantly lower in all SMPG groups except ≥130 mg/dL. Nocturnal and nocturnal documented hypoglycemia rates did not differ by treatment group. Hypoglycemia incidence did not differ by treatment in any SMPG group.Conclusion: In patients with T2D initiating basal insulin or previously treated for ≥6 months with basal insulin, Gla-300 provides similar efficacy to Gla-100 and reduces risk of hypoglycemia for many patients, despite a ~10% higher insulin dose.Abbreviations: A1C = glycated hemoglobin A1c; ADA = American Diabetes Association; Gla-100 = insulin glargine 100 U/mL; Gla-300 = insulin glargine 100 U/mL; OAD = oral antidiabetes drug; SMPG = self-monitored plasma glucose; T2D = type 2 diabetes     

Daily Inpatient Glycemic Survey (DINGS): A Process to Remotely Identify and Assist in the Management of Hospitalized Patients with Diabetes and Hyperglycemia

Objective: Hyperglycemia, hypoglycemia, and glycemic variability have been associated with increased morbidity, mortality, and overall costs of care in hospitalized patients. At the Stratton VA Medical Center in Albany, New York, a process aimed to improve inpatient glycemic control by remotely assisting primary care teams in the management of hyperglycemia and diabetes was designed.Methods: An electronic query comprised of hospitalized patients with glucose values <70 mg/dL or >350 mg/dL is generated daily. Electronic medical records (EMRs) are individually reviewed by diabetes specialist providers, and management recommendations are sent to primary care teams when applicable. Glucose data was retrospectively examined before and after the establishment of the daily inpatient glycemic survey (DINGS) process, and rates of hyperglycemia and hypoglycemia were compared.Results: Patient-day mean glucose slightly but significantly decreased from 177.6 ± 64.4 to 173.2 ± 59.4 mg/dL (P<.001). The percentage of patient-days with any value >350 mg/dL also decreased from 9.69 to 7.36% (P<.001), while the percentage of patient-days with mean glucose values in the range of 90 to 180 mg/dL increased from 58.1 to 61.4% (P<.001). Glycemic variability, assessed by the SD of glucose, significantly decreased from 53.9 to 49.8 mg/dL (P<.001). Moreover, rates of hypoglycemia (<70 mg/dL) decreased significantly by 41% (P<.001).Conclusion: Quality metrics of inpatient glycemic control improved significantly after the establishment of the DINGS process within our facility. Prospective controlled studies are needed to confirm a causal association.Abbreviations: DINGS = daily inpatient glycemic survey EMR = electronic medical record HbA1c = glycated hemoglobin ICU = intensive care unit VA = Veterans Affairs     

Proactive Protocol-Based Management of Hyperglycemia and Diabetes in Colorectal Surgery Patients

Objective: The management of diabetic patients undergoing elective abdominal surgery continues to be unsystematic, despite evidence that standardized perioperative glycemic control is associated with fewer postoperative surgical complications. We examined the efficacy of a pre-operative diabetes optimization protocol implemented at a single institution in improving perioperative glycemic control with a target blood glucose of 80 to 180 mg/dL.Methods: Patients with established and newly diagnosed diabetes who underwent elective colorectal surgery were included. The control group comprised 103 patients from January 1, 2011, through December 31, 2013, before protocol implementation. The glycemic-optimized group included 96 patients following protocol implementation from January 1, 2014, through July 31, 2016. Data included demographic information, blood glucose levels, insulin doses, hypoglycemic events, and clinical outcomes (length of stay, re-admissions, complications, and mortality).Results: Patients enrolled in the glycemic optimization protocol had significantly lower glucose levels intra-operatively (145.0 mg/dL vs. 158.1 mg/dL; P = .03) and postoperatively (135.6 mg/dL vs. 145.2 mg/dL; P = .005). A higher proportion of patients enrolled in the protocol received insulin than patients in the control group (0.63 vs. 0.48; P = .01), but the insulin was administered less frequently (median [interquartile range] number of times, 6.0 [2.0 to 11.0] vs. 7.0 [5.0 to 11.0]; P = .04). Two episodes of symptomatic hypoglycemia occurred in the control group. There was no difference in clinical outcomes.Conclusion: Improved peri-operative glycemic control was observed following implementation of a standardized institutional protocol for managing diabetic patients undergoing elective colorectal surgery.Abbreviations: HbA1c = glycated hemoglobin A1c; IQR = interquartile range     

Safety And Efficacy Of Dpp-4 Inhibitors For The Management Of Hospitalized General Medicine And Surgery Patients with Type 2 Diabetes

Objective: DPP-4 inhibitors (DPP-4i) have been shown to be effective for the management of inpatient diabetes. We report pooled data from 3 prospective studies using DPP-4i in general medicine and surgery patients with type 2 diabetes (T2D).Methods: We combined data from 3 randomized studies comparing DPP-4i alone or in combination with basal insulin or a basal-bolus insulin regimen. Medicine (n = 266) and surgery (n = 319) patients admitted with a blood glucose (BG) between 140 and 400 mg/dL, treated with diet, oral agents, or low-dose insulin therapy were included. Patients received DPP-4i alone (n = 144), DPP-4i plus basal insulin (n = 158) or basal-bolus regimen (n = 283). All groups received correctional doses with rapid-acting insulin for BG >140 mg/dL. The primary endpoint was differences in mean daily BG between groups. Secondary endpoints included differences in hypoglycemia and hospital complications.Results: There were no differences in mean hospital daily BG among patients treated with DPP-4i alone (170 ± 37 mg/dL), DPP-4i plus basal (172 ± 42 mg/dL), or basalbolus (172 ± 43 mg/dL), P = .94; or in the percentage of BG readings within target of 70 to 180 mg/dL (63 ± 32%, 60 ± 31%, and 64 ± 28%, respectively; P = .42). There were no differences in length of stay or complications, but hypoglycemia was less common with DPP-4i alone (2%) compared to DPP-4i plus basal (9%) and basal-bolus (10%); P = .004.Conclusion: Treatment with DPP-4i alone or in combination with basal insulin is effective and results in a lower incidence of hypoglycemia compared to a basal-bolus insulin regimen in general medicine and surgery patients with T2D.Abbreviations: BG = blood glucose; BMI = body mass index; CI = confidence interval; DPP-4i = dipeptidyl peptidase-4 inhibitors; HbA1c = hemoglobin A1c; OR = odds ratio; T2D = type 2 diabetes     

Fasting Versus Postprandial Hyperglycemia as a Treatment Target to Lower Elevated Hemoglobin A1C

Objective: Postprandial hyperglycemia (PPHG) may need addressing when glycemic control cannot be maintained in patients with type 2 diabetes mellitus. We investigated whether glycated hemoglobin A_1c (A_1c) levels ≥7.0% can indicate postprandial defects warranting prandial therapy after optimized basal insulin therapy.Methods: From 6 clinical trials of insulin glargine treatment, data were pooled from 496 patients with A_1c ≥7.0% after 24 weeks. Patient characteristics and clinical outcomes were summarized according to fasting plasma glucose (FPG) target achievement (<130 mg/dL), postprandial blood glucose (PPBG) levels, and PPBG increments (ΔPPBG). Basal and postprandial contributions to hyperglycemia were determined.Results: After 24 weeks of insulin glargine titration, A_1c change from baseline was greater in patients with FPG <130 mg/dL versus ≥130 mg/dL (-1.35% versus -1.11%, respectively; P = .0275), but with increased confirmed hypoglycemia rates (blood glucose <70 mg/dL; 4.06 events/patient-year versus 3.31 events/patient-year; P = .0170). However, increased severe hypoglycemia rates were observed in patients with FPG ≥130 mg/dL. At week 24, postprandial contributions to hyperglycemia increased (>60% regardless of PPBG). Patients with high FPG had lower, but substantial, relative postprandial contributions versus patients achieving FPG target. A similar pattern was observed according to whether patients had a ΔPPBG ≥50 mg/dL after any meal.Conclusion: After optimized basal insulin therapy, elevated A_1c is the most effective indicator of residual PPHG, regardless of existent FPG or PPBG. When confronted with an uncontrolled A_1c after reasonable titration of basal insulin, clinicians should be aware of probable postprandial contributions to hyperglycemia and consider prandial therapy.Abbreviations:A_1c = glycated hemoglobin A_1cAUC = area under the curveAUC_B = area under the curve (basal hyperglycemia)AUC_G = total area under the curve (total glucose)AUC_N = area under the curve (normal glycemic exposure)AUC_P = area under the curve (postprandial hyperglycemia)BHG = basal hyperglycemiaFBG = fasting blood glucoseFPG = fasting plasma glucoseGLP-1 = glucagon-like peptide 1HE = hyperglycemic exposureOADs = oral antidiabetes drugsPPBG = postprandial blood glucoseΔPPBG = change in postprandial blood glucosePPHG = postprandial hyperglycemiaSMBG = self-monitored blood glucoseT2DM = type 2 diabetes mellitus     

How Patients With Type 1 Diabetes Translate Continuous Glucose Monitoring Data into Diabetes Management Decisions

Objective: To understand how patients use continuous glucose monitoring (CGM) data in their diabetes management.Methods: We surveyed patients who regularly used CGM (>6 days per week), using 70 questions, many scenario-based. The survey had 6 sections: patient characteristics, general CGM use, hypoglycemia prevention and management, hyperglycemia prevention and management, insulin dosing adjustments (both for incidental hyperglycemia not at meals and at mealtimes), and real-time use versus retrospective analysis.Results: The survey was completed by 222 patients with type 1 diabetes. In response to a glucose of 220 mg/dL, the average correction dose adjustment based on rate of change arrows varied dramatically. Specifically, when the CGM device showed 2 arrows up (glucose increasing >3 mg/dL/minute), respondents stated they would increase their correction bolus, on average, by 140% (range, 0 to 600%). Conversely, 2 arrows down (glucose decreasing >3 mg/dL/minute) caused respondents to reduce their dose by 42%, with 24% omitting their dose entirely. Furthermore, 59% of respondents stated they would delay a meal in response to rapidly rising glucose, whereas 60% would wait until after a meal to bolus in response to falling glucose levels. With a glucose value of 120 mg/dL and a falling glucose trend, 70% of respondents would prophylactically consume carbohydrates to avoid hypoglycemia.Conclusion: CGM users utilize CGM data to alter multiple aspects of their diabetes care, including insulin dose timing, dose adjustments, and in hypoglycemia prevention. The insulin adjustments are much larger than common recommendations. Additional studies are needed to determine appropriate insulin adjustments based on glucose trend data.Abbreviations: A_1c = hemoglobin A_1c CGM = continuous glucose monitoring ROC = rate of change SMBG = self-monitored blood glucose     

Safety and Efficacy of a Peri-Operative Protocol for Patients with Diabetes Treated with Continuous Subcutaneous Insulin Infusion who are Admitted for Same-Day Surgery

Objective: The number of people with diabetes using continuous subcutaneous insulin infusions (CSII) with an insulin pump has risen dramatically, creating new challenges when these patients are admitted to the hospital for surgical or other procedures. There is limited literature guiding CSII use during surgical procedures.Methods: The study was carried out in a large, urban, tertiary care hospital. We enrolled 49 patients using insulin pump therapy presenting for 57 elective surgeries. We developed a CSII peri-operative glycemic management protocol (PGMP) to standardize insulin pump management in patients admitted to a same-day surgery unit (SDSU). The purpose was evaluate the safety (% capillary blood glucose (CBG) <70 mg/dL and/or pump incidents) and efficacy (first postoperative CBG ≤200 mg/dL) of the CSII PGMP. We determine the contribution of admission CBG, type of anesthesia, surgery length, and peri-operative steroid use on postoperative glycemic control.Results: Overall, 63% of patients treated according to the CSII PGMP had a first postoperative CBG ≤200 mg/dL. There were no episodes of intra- or postoperative hypoglycemia. For patients treated with the CSII PGMP, the mean postoperative CBG was lower in patients with anticipated or actual surgical length ≤120 minutes (158.1 ± 53.9 vs. 216 ± 77.7 mg/dL, P<.01). No differences were observed with admission CBG, type of anesthesia, or steroid use.Conclusions: This study demonstrates that a CSII PGMP is both safe and effective for patients admitted for elective surgical procedures and provides an example of a standardized protocol for use in clinical practice.Abbreviations: A1C = glycated hemoglobin BG = blood glucose CBG = capillary blood glucose CSII = continuous subcutaneous insulin infusion DM = diabetes mellitus EMR = electronic medical record IV = intravenous PGMP = peri-operative glycemic management protocol SDS = same-day surgery SDSU = same-day surgery unit SQ = subcutaneous UC = usual care     

Glycemic Effects Of Sglt-2 Inhibitor Canagliflozin In Type 1 Diabetes Patients Using The Dexcom G4 Platinum Cgm

Objective: Limited information is available on chronic use of sodium glucose cotransporter 2 inhibitors in type 1 diabetes (T1D). We conducted a retrospective review of T1D patients on Dexcom G4Platinum continuous glucose monitors (DCGMs) >1 year (mean, 4.6 years) who were prescribed canagliflozin (CANA) 100 mg daily and had a baseline DCGM 30-day download prior to and a second download after at least 1 month (mean, 3.7 months) taking CANA 100 mg daily. The glycemic, weight, and systolic blood pressure (SBP) effects are reported.Methods: We identified 27 patients meeting the selection criteria: 14 men; 25 white; 22 on pump; average T1D duration, 34 years (range, 12 to 48 years); average hemoglobin A1C (A1C), 7.6% (range, 6.1 to 9.8%); 22 with baseline A1C 7.0% or higher. All patients had an estimated glomerular filtration rate (eGFR) at baseline of 60 mL/min/1.73 m² or higher and were normotensive or on stable therapy. On average, 29 days of CGM data was reviewed. Total daily insulin dose (TDD) was available in 21 patients. We identified 27 patients who were judged to be candidates for CANA but did not have any change in glycemic therapy other than insulin adjustment as controls.Results: CANA resulted in significant reductions in mean blood glucose, CGM standard deviation, time in hyperglycemia, A1C, weight, SBP, and TDD, with increased time in target, with minimal increase in hypoglycemia and no significant change in eGFR. Three females developed genital mycotic infections but continued therapy, 2 developed ketoacidosis from insulin interruption.Conclusion: CANA offers promise as adjunct therapy in T1D, though caution is advised.Abbreviations:A1C = hemoglobin A1CCANA = canagliflozinCGM = continuous glucose monitorCSII = continuous subcutaneous insulin infusionDCGM = Dexcom G4Platinum CGMDKA = diabetic ketoacidosisGMI = genital mycotic infectionMG = mean glucosePCGM = personal continuous glucose monitoringSBP = systolic blood pressureSGLT-2i = sodium-glucose cotransporter 2 inhibitorSH = severe hypoglycemiaT2D = type 2 diabetesT1D = type 1 diabetes     

The Impact of GLP-1 Receptor Agonists on Patients with Diabetes on Insulin Therapy

Objective: The clinical benefit of adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) to basal-bolus or very high dose insulin regimens is unclear. This study investigated the impact of adding a GLP-1RA to a spectrum of insulin regimens (basal, basal-bolus, and U-500) to determine the impact on hemoglobin A1c (HbA1c), weight loss, and total daily insulin dose (TDD) over the course of 12 months.Methods: A retrospective chart review was conducted on 113 participants with type 2 diabetes mellitus using insulin therapy. Each participant's HbA1c, body weight, and TDD were recorded prior to initiation of GLP-1RA therapy and at the 3, 6, and 12-month time points while on combination therapy.Results: Across all participants, the HbA1c values decreased significantly from a baseline of 8.9 (74 mmol/mol) ± 0.14% to 8.2 (66 mmol/mol) ± 0.14% (P<.01) in the first 3 months, 8.0 (64 mmol/mol) ± 0.12% (P<.01) at 6 months, to 8.3 (67 mmol/mol) ± 0.14% (P<.01) at 12 months. There was no significant decrease in weight or TDD with the addition of a GLP-1RA overall or in different insulin groups. However, there was a clinically significant decrease in weight over the study duration.Conclusion: The results of this study suggest that adding a GLP-1RA to various insulin regimens may help to achieve glycemic goals while avoiding the less desirable side effects of weight gain and increasing insulin regimens. However, the expected weight loss and decrease in TDD may not be as sizable in the clinical setting.Abbreviations: DCOE = Diabetes Center of Excellence; DM = diabetes mellitus; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = hemoglobin A1c; RCT = randomized controlled trial; TDD = total daily dose     

Addressing Pitfalls in Management of Diabetic Ketoacidosis with a Standardized Protocol

Objective: To determine the efficacy and safety of a diabetic ketoacidosis (DKA)-Power Plan (PP) for guiding intravenous (IV) insulin infusions prior to anion gap (AG) closure and administering subcutaneous (SC) insulin ≥1 hour before discontinuing IV insulin.Methods: Retrospective chart review of patients with DKA before (pre-PP) (n = 60) and following (post-PP) (n = 60) implementation of a DKA-PP. Groups were compared for percentage of patients for whom IV insulin therapy was continued until AG closure, the percentage of patients receiving SC insulin ≥1 hour before discontinuation of IV insulin, and percentage of patients with rebound DKA during the index hospitalization.Results: Admission plasma glucose (514 mg/dL vs. 500 mg/dL; P = .36) and venous pH (7.2 vs. 7.2; P = .57) were similar in pre- and post-PP groups. Inappropriate discontinuation of IV insulin occurred less frequently in post-PP patients (28% vs. 7%; P = .007), with a lower frequency of rebound DKA (40% vs. 8%; P = .001) following acute management. More post-PP patients received SC insulin ≥1 hour before discontinuation of IV insulin (65% vs. 78%; P = .05).Conclusion: Implementation of a DKA-PP was associated with appropriate discontinuation of IV insulin in more patients, more frequent administration of SC insulin ≥1 hour prior to discontinuation of IV insulin, and fewer episodes of rebound DKA.Abbreviations: ADA = American Diabetes Association; AG = anion gap; BG = blood glucose; DKA = diabetic ketoacidosis; DKA-PP = DKA-Power Plan; ICU = intensive care unit; IQR = interquartile range; IV = intravenous; IVF = IV fluid; LOS = length of stay; SC = subcutaneous     

Basal-Bolus Regimen With Insulin Analogues Versus Human Insulin in Medical Patients with type 2 Diabetes: A Randomized Controlled Trial in Latin America

Objective: Few randomized studies have focused on the optimal management of non–intensive care unit patients with type 2 diabetes in Latin America. We compared the safety and efficacy of a basal-bolus regimen with analogues and human insulins in general medicine patients admitted to a University Hospital in Asunción, Paraguay.Methods: In a prospective, open-label trial, we randomized 134 nonsurgical patients with blood glucose (BG) between 140 and 400 mg/dL to a basal-bolus regimen with glargine once daily and glulisine before meals (n = 66) or Neutral Protamine Hagedorn (NPH) twice daily and regular insulin before meals (n = 68). Major outcomes included differences in daily BG levels and frequency of hypoglycemic events between treatment groups.Results: There were no differences in the mean daily BG (157 ± 37 mg/dL versus 158 ± 44 mg/dL; P = .90) or in the number of BG readings within target <140 mg/dL before meals (76% versus 74%) between the glargine/glulisine and NPH/regular regimens. The mean insulin dose in the glargine/glulisine group was 0.76 ± 0.3 units/kg/day (glargine, 22 ± 9 units/day; glulisine, 31 ± 12 units/day) and was not different compared with NPH/regular group (0.75 ± 0.3 units/kg/day [NPH, 28 ± 12 units/day; regular, 23 ± 9 units/day]). The overall prevalence of hypoglycemia (<70 mg/dL) was similar between patients treated with NPH/regular and glargine/glulisine (38% versus 35%; P = .68), but more patients treated with human insulin had severe (<40 mg/dL) hypoglycemia (7.6% versus 25%; P = .08). There were no differences in length of hospital stay or mortality between groups.Conclusion: The basal-bolus regimen with insulin analogues resulted in equivalent glycemic control and frequency of hypoglycemia compared to treatment with human insulin in hospitalized patients with diabetes.Abbreviations: BG = blood glucose BMI = body mass index HbA_1c = glycated hemoglobin NPH = Neutral Protamine Hagedorn T2D = type 2 diabetes     

Clinical Efficacy and Patient Satisfaction with U-500 Insulin Pump Therapy in Patients with Type 2 Diabetes

ObjectiveTo determine the safety and efficacy of U-500 regular insulin in pump therapy and to assess satisfaction with U-500 insulin pump therapy in patients with type 2 diabetes and severe insulin resistance.MethodsWe performed a retrospective review of medical records of 6 patients with type 2 diabetes and insulin resistance who had been using U-500 insulin pump therapy for at least 6 months. In addition, we conducted a telephone follow-up patient satisfaction survey.ResultsThe mean age of the patients was 57 ± 6 years. Of the 6 patients (3 men and 3 women), 4 were white, 1 was black, and 1 was Asian. The mean hemoglobin A1c value before continuous subcutaneous insulin infusion therapy with U-500 regular insulin was 9.1% ± 1.8%, and the mean U-100 insulin dose required was 391 ± 91 U/day. In comparison, the mean U-500 insulin dose required at 6 months was 59.2 ± 13.6 U/day, which is equivalent to 296 ± 68 U/day of U-100 insulin (P = 0.04), and the mean hemoglobin A1c value at 6 months after treatment with the insulin pump using U-500 regular insulin was 6.9% ± 0.9% (P = 0.03). In addition, our study patients lost a mean of 6.1 lb during the 6-month period, and no patient had clinically significant episodes of hypoglycemia. The majority of the patients reported a higher satisfaction with the U-500 insulin pump therapy in comparison with conventional insulin treatment.ConclusionU-500 insulin pump therapy is a novel alternative for patients with type 2 diabetes and severe insulin resistance who have not met glycemic control goals with use of standard intensive insulin regimens. (Endocr Pract. 2007;13:721-725)     

Effects of a Computerized Order Set on the Inpatient Management of Hyperglycemia: A Cluster-Randomized Controlled Trial

ObjectiveTo determine the effects of a computerized order set on the inpatient management of diabetes and hyperglycemia.MethodsWe conducted a cluster-randomized controlled trial on the general medical service of an academic medical center staffed by residents and hospitalists. Consecutively enrolled patients with diabetes mellitus or inpatient hyperglycemia were randomized on the basis of their medical team to usual care (control group) or an admission order set built into the hospital’s computer provider order entry (CPOE) system (intervention group). All teams received a detailed subcutaneous insulin protocol and case-based education. The primary outcome was the mean percent of glucose readings per patient between 60 and 180 mg/dL.ResultsBetween April 5 and June 22, 2006, we identified 179 eligible study subjects. The mean percent of glucose readings per patient between 60 and 180 mg/dL was 75% in the intervention group and 71% in the usual care group (adjusted relative risk, 1.36; 95% confidence interval, 1.03 to 1.80). In comparison with usual care, the intervention group also had a lower patient-day weighted mean glucose (148 mg/dL versus 158 mg/dL, P = .04), less use of sliding-scale insulin by itself (25% versus 58%, P = .01), and no significant difference in the rate of severe hypoglycemia (glucose < 40 mg/dL; 0.5% versus 0.3% of patient-days, P = .58).ConclusionThe use of an order set built into a hospital’s CPOE system led to improvements in glycemic control and insulin ordering without causing a significant increase in hypoglycemia. Other institutions with CPOE should consider adopting similar order sets as part of a comprehensive inpatient glycemic management program. (Endocr Pract. 2010;16:209-218)     

Use of U-500 insulin in the treatment of severe insulin resistance

Background: Glycemic control is essential in the management of diabetes. However, many patients with diabetes are not achieving therapeutic targets, partly because they are receiving insufficient doses of insulin. This is particularly problematic in patients with severe insulin resistance, defined as insulin requirement >200 units/kg per day (>3 units/kg per day for pediatric patients). It is difficult to use U-100 forms of insulin at doses >200 units/kg per day because of the volume of insulin being administered subcutaneously. U-500, a concentrated form of insulin, may be useful in the treatment of these patients.Objective: Current practice regarding the use of U-500 insulin has been published elsewhere. This article presents an updated algorithm for the administration and dosing of U-500 insulin, based on clinical experience with severe forms of insulin resistance. Guidelines are provided for dose escalation of U-500 insulin.Methods: We reviewed the results of treatment with U-500 insulin in patients with severe insulin resistance. We analyzed the results, updated a pre-existing algorithm, provided additional practical information on the administration and dosing of U-500 insulin, and compared the cost of U-500 with that of U-100 insulin.Results: To date, we have treated 56 patients (age range, 9–54 years) with severe insulin resistance using U-500 insulin. Doses ranged from 1.5 to 566 units/kg per day. Based on the pharmacodynamic properties of U-500 insulin, this concentrated form must be administered and dosed differently than regular U-100 insulin. U-500 insulin cost more than U-100 insulin on a per-milliliter basis, but cost less in the end because of the lower volumes of insulin required and fewer syringes and pump cartridges needed to administer U-500 insulin.Conclusions: In our experience, U-500 insulin is a useful tool in the management of patients with severe insulin resistance. U-500 insulin alleviates the volume-related problems associated with U-100 insulin, making treatment with higher doses of insulin (≥200 units per day) more effective with U-500 insulin than with U-100 insulin.     

The Effect of Prestudy Insulin Therapy on Safety and Efficacy of Human Regular U-500 Insulin by Pump or Injection: A Posthoc Analysis

ObjectiveWe conducted a posthoc analysis of the VIVID study (Safety and Efficacy of Human Regular U-500 Insulin Administered by Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections in Subjects With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Parallel Clinical Trial), comparing 2 delivery methods of human regular U-500 insulin (U-500R), continuous subcutaneous insulin infusion (CSII) versus multiple daily injection (MDI), in type 2 diabetes requiring high insulin, to determine influence of prestudy insulin on glycemic outcomes.MethodsWe compared A1C, total daily insulin dose (TDD), weight, and hypoglycemia by subgroups of prestudy insulin (prestudy U-500R vs non-U-500R) and treatment (CSII vs MDI).ResultsAt baseline, prestudy U-500R had higher TDD, higher body mass index, lower A1C and fasting plasma glucose, and higher rate of hypoglycemia compared to non-U-500R. Active titration of U-500R reduced A1C in both subgroups, with maximum benefit at 8 weeks. At 26 weeks, CSII provided the greatest reduction in A1C in both subgroups, with a greater reduction in non-U-500R. MDI provided an A1C reduction in both subgroups, with the greater reduction in non-U-500R. At 8 weeks, prestudy U-500R reached its lowest A1C; thereafter, A1C rebounded with MDI and remained stable with CSII. In non-U-500R, A1C continued to decrease to study end. In non-U-500R, hypoglycemia increased during active titration, but then decreased in the posttitration maintenance period. In both subgroups, TDD increased from baseline with MDI but not with CSII. Body weight increased in both subgroups but was greater in prestudy U-500R with CSII compared to MDI.ConclusionRegardless of previous insulin, people on high-dose insulin could lower A1C with U-500R, with additional benefit from CSII. These results may provide guidance for use of U-500R in clinical practice.