Basal Insulin Degludec and Glycemic Control Compared to Aspart Via Insulin Pump in Type 1 Diabetes (BIGLEAP): A Single-Center, Open-Label, Randomized, Crossover Trial.

OBJECTIVE: We compared the efficacy of the second-generation basal insulin degludec (IDeg) to that of insulin aspart via pump using continuous glucose monitoring in patients with well-controlled type 1 diabetes. METHODS: In this 40-week, single-center, randomized, crossover-controlled trial, adults with well-controlled type 1 diabetes (hemoglobin A1C of <7.5% [<58 mmol/mol]) (N = 52) who were using an insulin pump and continuous glucose monitoring were randomized to 1 of 2 treatments for a 20-week period: a single daily injection of IDeg with bolus aspart via pump or a continuous subcutaneous insulin infusion (CSII) with aspart, followed by crossover to the other treatment. The primary endpoint was time in range (70-180 mg/dL) during the final 2 weeks of each treatment period. RESULTS: Fifty-two patients were randomized and completed both treatment periods. The time in range for IDeg and CSII was 71.5% and 70.9%, respectively (P = .553). The time in level 1 hypoglycemia for the 24-hour period with IDeg and CSII was 2.19% and 1.75%, respectively (P = .065). The time in level 2 hypoglycemia for the 24-hour period with IDeg and CSII was 0.355% and 0.271%, respectively (P = .212), and the nocturnal period was 0.330% and 0.381%, respectively (P = .639). The mean standard deviation of blood glucose levels for the 24-hour period for IDeg and CSII was 52.4 mg/dL and 51.0 mg/dL, respectively (P = .294). The final hemoglobin A1C level for each treatment was 7.04% (53 mmol/mol) with IDeg, and 6.95% (52 mmol/mol) with CSII (P = .288). Adverse events were similar between treatments. CONCLUSION: We observed similar glycemic control between IDeg and insulin aspart via CSII for basal insulin coverage in patients with well-controlled type 1 diabetes.

A Randomized Trial Evaluating the Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec With or Without Metformin, in Adults With Type 2 Diabetes (ONSET 9).

OBJECTIVE: To evaluate the efficacy and safety of fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp), both with insulin degludec with or without metformin, in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen. RESEARCH DESIGN AND METHODS: This multicenter, double-blind, treat-to-target trial randomized participants to faster aspart (n = 546) or IAsp (n = 545). All available information, regardless of treatment discontinuation or use of ancillary treatment, was used for evaluation of effect. RESULTS: Noninferiority for the change from baseline in HbA1c 16 weeks after randomization (primary end point) was confirmed for faster aspart versus IAsp (estimated treatment difference [ETD] -0.04% [95% CI -0.11; 0.03]; -0.39 mmol/mol [-1.15; 0.37]; P < 0.001). Faster aspart was superior to IAsp for change from baseline in 1-h postprandial glucose (PPG) increment using a meal test (ETD -0.40 mmol/L [-0.66; -0.14]; -7.23 mg/dL [-11.92; -2.55]; P = 0.001 for superiority). Change from baseline in self-measured 1-h PPG increment for the mean over all meals favored faster aspart (ETD -0.25 mmol/L [-0.42; -0.09]); -4.58 mg/dL [-7.59; -1.57]; P = 0.003). The overall rate of treatment-emergent severe or blood glucose (BG)-confirmed hypoglycemia was statistically significantly lower for faster aspart versus IAsp (estimated treatment ratio 0.81 [95% CI 0.68; 0.97]). CONCLUSIONS: In combination with insulin degludec, faster aspart provided effective overall glycemic control, superior PPG control, and a lower rate of severe or BG-confirmed hypoglycemia versus IAsp in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen.

Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American inTandem1 Study.

OBJECTIVE: Evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized insulin in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: The inTandem1 trial, a double-blind, 52-week phase 3 trial, randomized North American adults with T1D to placebo (n = 268), sotagliflozin 200 mg (n = 263), or sotagliflozin 400 mg (n = 262) after 6 weeks of insulin optimization. The primary end point was HbA1c change from baseline at 24 weeks. HbA1c, weight, and safety were also assessed through 52 weeks. RESULTS: From a mean baseline of 7.57%, placebo-adjusted HbA1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P < 0.001). Among patients with a baseline HbA1c ≥7.0%, an HbA1c <7% was achieved by 15.7%, 27.2%, and 40.3% of patients receiving placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively (P ≤ 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences between sotagliflozin 400 mg and placebo were -1.08 mmol/L for fasting plasma glucose, -4.32 kg for weight, and -15.63% for bolus insulin dose and -11.87% for basal insulin dose (all P < 0.001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly by 2.5 points with sotagliflozin versus placebo (P < 0.001) at 24 weeks. Genital mycotic infections and diarrhea occurred more frequently with sotagliflozin. Adjudicated diabetic ketoacidosis (DKA) occurred in 9 (3.4%) and 11 (4.2%) patients receiving sotagliflozin 200 and 400 mg, respectively, and in 1 (0.4%) receiving placebo. Severe hypoglycemia occurred in 17 (6.5%) patients from each sotagliflozin group and 26 (9.7%) patients receiving placebo. CONCLUSIONS: In a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo (ClinicalTrials.gov, NCT02384941).

Insulin degludec versus insulin glargine U100 for patients with type 1 or type 2 diabetes in the US: a budget impact analysis with rebate tables.

BACKGROUND AND AIMS: Drug rebates are almost universally negotiated privately between the manufacturer and the payer in the US. The aim of the present study was to illustrate the use of a "rebate table" to improve the transparency and utility of published budget impact analyses in the US by modeling ranges of hypothetical rebates for two comparators. Worked examples were conducted to illustrate the budgetary implications of using insulin degludec (IDeg) relative to insulin glargine (IGlar) U100 in patients with type 1 or 2 diabetes. METHODS: A short-term (1-year) budget impact model was developed to evaluate the costs of switching to IDeg from IGlar in patients with type 1 or 2 diabetes on basal-bolus and basal-only insulin, respectively. The analysis used insulin dose and hypoglycemia data from recent randomized trials, data on the prevalence of diabetes, and estimates of the proportion of patients using each insulin regimen. The model was configured to run multiple rebate scenarios to generate a rebate table in a hypothetical 1 million member commercial plan. RESULTS: Relative to IGlar, IDeg resulted in reductions in non-severe and severe hypoglycemia incidence and costs both in patients with type 1 and patients with type 2 diabetes. Insulin acquisition costs were higher, and respective rebates of 7.3% and 10.6% were required for IDeg to break-even with IGlar at the full list price. Incremental per member per month IDeg costs without a rebate were USD 0.04 in type 1 diabetes and USD 0.80 in type 2 diabetes. CONCLUSIONS: Using IDeg instead of IGlar at list price could result in a modest increase in costs when considering insulin and hypoglycemia costs alone, but modest incremental rebates with IDeg would result in cost neutrality relative to IGlar. In addition, IDeg would result in reduced incidence of severe and non-severe hypoglycemia.

The effect of long-term use of U-500 insulin via continuous subcutaneous infusion on durability of glycemic control and weight in obese, insulin-resistant patients with type 2 diabetes.

OBJECTIVE: To evaluate the long-term efficacy and safety of U-500 insulin administered via continuous subcutaneous insulin infusion (CSII) in patients with insulin-resistant type 2 diabetes and high insulin requirements. METHODS: We retrospectively reviewed the effects of U-500 insulin administered via CSII on durability of glycemic control (HbA1c), body weight, total daily insulin dose, and incidence of hypoglycemia in 59 patients with insulin-resistant type 2 diabetes (duration of treatment 1 to 9.5 years; mean treatment duration 49 months). All variables were analyzed by 1-way analysis of variance (ANOVA) from pre-U-500 baseline to time points from 3 to 114 months. RESULTS: After 3 months of U-500 insulin use, hemoglobin A1c dropped significantly from a mean baseline of 8.3% to a mean value of 7.3% (P = .003), and this improvement was sustained for over 66 months of use. There was no significant overall change in body weight or total daily insulin dose over time with the use of U-500 insulin. For those subjects who did gain weight, there was a parallel increase in insulin dose that correlated with weight gain. The overall incidence of severe hypoglycemia was low over the study period, with a mean occurrence of 0.1 episodes per patient per year. CONCLUSIONS: U-500 insulin is safe and effective for extended use (up to 9.5 years) in patients with insulin-resistant type 2 diabetes who require high insulin doses, and provides sustained glycemic control without causing excessive weight gain.

Successful management of differentiated thyroid cancer in a community-based endocrine practice.

OBJECTIVE: To describe the range of differentiated thyroid cancer (DTC) cases, disease complexity, and treatment outcomes seen in our 3-physician community-based general endocrine practice during an 8-year period in order to make comparisons with published cohorts from university settings. METHODS: Medical records of patients with DTC treated between 2002 and 2009 at Mountain Diabetes and Endocrine Center (Asheville, North Carolina) were reviewed. Pathologic features, staging, and disease status at last contact were determined. Multivariate analyses of adverse prognostic risk factors at diagnosis, recombinant human thyroid-stimulating hormone use, and radioiodine use were compared with the ultimate outcome of patients. RESULTS: We treated a total of 167 patients with DTC during the study period (mean age at diagnosis, 44.4 years; mean duration of follow-up, 6.2 years). In our study cohort, 88.6% had papillary thyroid cancer, 74% had stage I disease, and 32.4% of those with papillary thyroid cancer had microscopic tumors (≤1 cm). Remission occurred in 67.1%, 17.1% had persistent disease, and 11.8% were indeterminate for remission; non-thyroid cancer death occurred in 2.6% and disease-specific death in 1.3%. The mean number of adverse prognostic risk factors per patient was 2.0 in those with remission and 4.7 in those with persistent disease. CONCLUSION: Community-based endocrinologists evaluate the full spectrum of thyroid cancer disease complexity and can achieve excellent outcomes. In our current study group, disease persistence and disease-specific death occurred in 17.1% and 1.3%, respectively. Individualization of care based on prognostic variables guided our diagnostic and therapeutic decisions.

A prospective trial of U500 insulin delivered by Omnipod in patients with type 2 diabetes mellitus and severe insulin resistance.

OBJECTIVE: To test the effectiveness and safety of U500 regular insulin delivered by continuous subcutaneous insulin infusion (CSII) via the Omnipod insulin delivery system in patients with uncontrolled type 2 diabetes mellitus and severe insulin resistance. METHODS: In this prospective, 1-year, proof-of-concept trial, patients with insulin-requiring type 2 diabetes who had a hemoglobin A1c level of 7.0% or higher and severe insulin resistance (average insulin requirement, 1.74 units of insulin per kilogram each day; range, 1.4 to 2.64 units of insulin per kilogram [average insulin dose, 196.4 units daily]) were identified at routine office visits at Mountain Diabetes and Endocrine Center in Asheville, North Carolina, between December 2007 and August 2008. All patients had been on intensive insulin therapy with or without oral agents for more than 3 months. All patients were switched from baseline failed therapy to U500 regular insulin by continuous subcutaneous insulin infusion via Omnipod. Effectiveness was assessed by hemoglobin A1c measurement and 72-hour continuous glucose monitoring at baseline and at weeks 13, 26, and, 52 and by treatment satisfaction assessed by the Insulin Delivery Rating System Questionnaire at baseline and at week 52 while on U500 via Omnipod. RESULTS: Twenty-one adults were enrolled (mean age, 54 years; mean duration of diabetes, 4 years; mean body mass index, 39.4 kg/m2; mean insulin requirement, 1.7 U/kg per day; and mean hemoglobin A1c, 8.6%) whose previous treatment with U100 insulin regimens had failed. Twenty patients completed the study. Treatment with U500 insulin via Omnipod significantly reduced hemoglobin A1c by 1.23% (P<.001) and significantly increased the percentage of time spent in the blood glucose target range (70-180 mg/dL) by 70.75% as assessed by continuous glucose monitoring (P<.001) without a significant increase in hypoglycemia. Patients were satisfied with treatment with U500 insulin via Omnipod, and 14 patients elected to remain on treatment at study completion. CONCLUSIONS: U500 insulin delivered subcutaneously continuously via Omnipod is a safe and effective method of insulin delivery in the very insulin-resistant type 2 diabetic population.

High-dose insulin therapy: is it time for U-500 insulin?

OBJECTIVE: To provide an overview of U-500 regular insulin action, review published clinical studies with U-500 regular insulin, and offer guidance to practicing endocrinologists for identifying patients for whom U-500 regular insulin may be appropriate. METHODS: This review has been produced through a synthesis of relevant published literature compiled via a literature search (MEDLINE search of the English-language literature published between January 1969, and July 2008, related to U-500, insulin resistance, concentrated insulin, high-dose insulin, insulin pharmacokinetics, and diabetes management) and the authors' collective clinical experience. RESULTS: The obesity epidemic is contributing to an increase in the prevalence of type 2 diabetes, as well as to increasing insulin requirements in insulin-treated patients. Many of these patients exhibit severe insulin resistance, manifested by daily insulin requirements of 200 units or greater or more than 2 units/kg. Delivering an appropriate insulin volume to these patients can be difficult and inconvenient and may be best accomplished with U-500 regular insulin by multiple daily injections or with continuous subcutaneous insulin infusion, rather than with standard U-100 insulin. Implementation of U-500 regular insulin in patients previously on other insulin formulations is described with a treatment algorithm covering dosage requirements ranging from 150 to more than 600 units per day on the basis of the authors' experience. CONCLUSIONS: Regimen conversion of appropriately selected patients from high-dose, U-100 insulin to U-500 regular insulin therapy on the basis of the recommendations presented in this article may potentially result in improved glycemic control and lower cost.

Use of U-500 regular insulin by continuous subcutaneous insulin infusion in patients with type 2 diabetes and severe insulin resistance.

OBJECTIVE: To determine the safety and efficacy of U-500 regular insulin delivered by continuous subcutaneous insulin infusion (CSII) as treatment for patients with type 2 diabetes and severe insulin resistance (mean 24-hour insulin requirement, 1.46 U/kg daily) who had failure of previous insulin therapy with either multiple daily injection (MDI) regimens or CSII using U-100 insulin analogues. METHODS: The study group consisted of 9 patients with type 2 diabetes and severe insulin resistance with hemoglobin A1c (A1C) values that exceeded 7.0%. All patients had been previously treated with MDI regimens with either glargine or NPH insulin plus insulin lispro, insulin aspart, or U-500 regular insulin before meals or CSII with insulin lispro or aspart. Treatment was changed to U-500 regular insulin by CSII with use of one of the following insulin pumps: MiniMed 508, Medtronic-MiniMed Paradigm 511, or Deltec Cozmo. A1C, weight, and total daily insulin dose were determined at baseline and after 3 months of CSII with U-500 regular insulin. Statistical comparisons were made by using a paired t test. RESULTS: After 3 months, treatment with U-500 regular insulin by CSII resulted in a statistically significant mean decrease in A1C (P = 0.026) of 1.14%, a marginal mean increase in weight of 4.1 lb (P = 0.078), no significant change in total daily insulin dose (P = 0.622), and no clinically significant hypoglycemic episodes. Moreover, all study patients preferred the new treatment option over their previous regimens. CONCLUSION: U-500 regular insulin by CSII is a safe and effective therapeutic intervention for patients with type 2 diabetes who have had treatment failure with MDI insulin regimens or CSII with use of U-100 insulin or insulin analogues.

Continuous subcutaneous insulin infusion (CSII) of insulin aspart versus multiple daily injection of insulin aspart/insulin glargine in type 1 diabetic patients previously treated with CSII.

OBJECTIVE: Multiple daily injection (MDI) therapy of bolus insulin aspart and basal insulin glargine was compared with continuous subcutaneous insulin infusion (CSII) with aspart in type 1 diabetic patients previously treated with CSII. RESEARCH DESIGN AND METHODS: One hundred patients were enrolled in a randomized, multicenter, open-label, crossover study. After a 1-week run-in period with aspart by CSII, 50 subjects were randomly assigned to MDI therapy (aspart immediately before each meal and glargine at bedtime) and 50 subjects continued CSII. After 5 weeks of the first treatment, subjects crossed over to the alternate treatment for 5 weeks. During the last week of each treatment period, subjects wore a continuous glucose monitoring system for 48-72 h. RESULTS: Mean serum fructosamine levels were significantly lower after CSII therapy than after MDI therapy (343 +/- 47 vs. 355 +/- 50 micromol/l, respectively; P = 0.0001). Continuous glucose monitoring profiles over a 24-h time period showed that glucose exposure was 24 and 40% lower for CSII than MDI as measured by area under the curve (AUC) glucose >/=80 mg/dl (1,270 +/- 742 vs. 1,664 +/- 1,039 mg . h . dl(-1); P < 0.001) and AUC glucose >/=140 mg/dl (464 +/- 452 vs. 777 +/- 746 mg . h . dl(-1), CSII vs. MDI, respectively; P < 0.001). Similar percentages of subjects reported hypoglycemic episodes (CSII: 92%, MDI: 94%) and nocturnal (12:00 a.m. to 8:00 a.m.) hypoglycemic episodes (CSII: 73%, MDI: 72%). Major hypoglycemia was infrequent (CSII: two episodes, MDI: five episodes). CONCLUSIONS: In a trial of short duration, CSII therapy with insulin aspart resulted in lower glycemic exposure without increased risk of hypoglycemia, as compared with MDI with insulin aspart and glargine.