Treatment Patterns, Adherence, and Persistence Associated With Human Regular U-500 Insulin: A Real-World Evidence Study.

OBJECTIVE | Human regular U-500 insulin (U-500R) is concentrated insulin with basal and prandial activity that can be used as insulin monotherapy. The goal of this study was to better understand treatment patterns (total daily dose [TDD] and concomitant medications), adherence, and persistence in real-world patients treated with U-500R. DESIGN AND METHODS | We selected patients from the Truven Health MarketScan database who initiated U-500R between 2010 and 2013. We collected data for three periods: pre-index (12 months before initiation), post-index (12 months after initiation or until a gap of ≥60 days in U-500R claims), and follow-up (12 months after post-index). Data were analyzed using descriptive statistics and a regression model as appropriate. RESULTS | We identified 1,582 patients who met the selection criteria. The median TDD of U-500R during the post-index period was 333 units/day, with 70.0% of patients using 300-400 units/day. During the post-index period, 74.1% of patients had U-500R claims that did not overlap with prescriptions for other insulins, interpreted as U-500R monotherapy. Among patients with ≥1 U-500R fill in the post-index period (n = 1,208), 54.4% had a medication possession ratio (MPR, a measure of adherence) ≥80%. Although 849 patients had a gap of ≥60 days in U-500R claims in the post-index period, 602 of those resumed U-500R in the follow-up period. Of the 733 patients who had no gap in U-500R claims in the post-index period, 286 had a gap of ≥60 days in claims in year 2, and 447 continued with U-500R treatment beyond 2 years. CONCLUSION | These results demonstrate that U-500R was commonly used as insulin monotherapy, with a median TDD >300 units/day. Compared with published, relevant studies of other insulins, U-500R showed similar or greater adherence and persistence rates. These new data may help guide clinical decision-making when choosing insulin therapy for patients requiring high doses of insulin.

EFFECT OF TOTAL DAILY DOSE ON EFFICACY, DOSING, AND SAFETY OF 2 DOSE TITRATION REGIMENS OF HUMAN REGULAR U500 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 thricedaily (TID) and twice-daily (BID) U-500R in 325 patients transitioned from high-dose/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 event BID = twice daily HbA1c = glycated hemoglobin QID = 4 times daily RCT = randomized clinical trial 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 ß-CELL FUNCTION IN SEVERELY INSULIN-RESISTANT PATIENTS WITH LONG-STANDING TYPE 2 DIABETES AND HIGH INSULIN REQUIREMENTS.

OBJECTIVE: To assess ß-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/m(2); glycated hemoglobin [HbA1c], 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 (AUCC-peptide/AUCglucose) at 24-week endpoint. RESULTS: Change from baseline HbA1c, daily U-500R dose, and weight were -1.17% (P = .0002), +80.8 units (P = .0003), and +5.9 kg (P = .33), respectively. ß-Cell function significantly improved after 24 weeks of U-500R therapy in combined treatment groups. The AUCC-peptide/AUCglucose 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/m(2), and glucose sensitivity improved from 18.3 to 24.0 pmol/min/m(2)/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 ß-cells was observed with improved glycemic control in these severely insulin-resistant patients with T2D, possibly due to alleviation of glucotoxicity.

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/m(2); glycated hemoglobin [HbA1c], 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 HbA1c change from baseline. RESULTS: After 24 weeks, both treatments demonstrated significant HbA1c 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.

Healthcare costs and adherence associated with human regular U-500 versus high-dose U-100 insulin in patients with diabetes.

OBJECTIVE: Describe the characteristics, costs, and adherence of patients receiving human regular U-500 insulin (U-500R) compared with those of patients receiving high-dose (≥150 units/day) U-100 insulin. METHODS: Data from Truven Health MarketScan Research Databases, July 1, 2008, through December 31, 2010, were used. The U-100 cohort received ≥150 units/day of U-100 insulin for ≥31 days during the first 60 days after the index date. The U-500R cohort received ≥2 prescriptions of U-500R after the index date. Analyses were performed on propensity-matched cohorts. The changes in annualized costs were compared between the 2 cohorts using paired t tests. Adherence was assessed by the proportion of days covered (PDC) and compared using a 2-sample t test. Glycemic efficacy data were not available in this database. RESULTS: There were 1,044 U-500R-treated patients (19.1% with type 1 diabetes [T1D]) and 11,520 U-100-treated patients (23.8% with T1D) identified, from which 1,039 matched pairs were obtained. The mean decrease of $1,290 in annual pharmacy costs for the U-500R cohort was significantly different from the mean increase of $2,586 for the U-100 cohort (P<.001; 95% confidence interval, -$4,345 to -$3,422). More U-500R patients experienced hypoglycemia (17.3% vs. 11.8%; P<.001), but the hypoglycemia rate per person and related costs were not significantly different between cohorts. Finally, the mean 12-month PDC was 65.0% for U-500R versus 47.6% for U-100 patients (P<.0001). CONCLUSION: Compared with treatment with ≥150 units/day of U-100 insulin, treatment with U-500R was associated with decreases in pharmacy costs, a higher percentage of patients experiencing hypoglycemia, and greater treatment adherence.

Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered via Continuous Subcutaneous Insulin Infusion Versus Subcutaneous Injection in Adults With Type 2 Diabetes and High-Dose Insulin Requirements.

INTRODUCTION: Human regular U-500 insulin (U-500R) is approved for subcutaneous (SC) injection in patients with diabetes requiring >200 units/day of insulin. Here, pharmacokinetic and pharmacodynamic (PK/PD) profiles following U-500R administered by continuous subcutaneous insulin infusion (CSII) and SC injection in adults with type 2 diabetes (T2D) on high-dose insulin were studied. METHODS: In this randomized, crossover, euglycemic clamp study, patients received a 100-unit bolus of U-500R via SC injection or CSII with basal infusion using a U-500R specific pump. PK parameters were estimated using non-compartmental methods. PD estimates were derived from the glucose infusion rate during the euglycemic clamp procedure. RESULTS: When corrected for the basal infusion, the PK profiles for the 100-unit bolus of U-500R were similar for CSII and SC injection. Without correction for basal infusion, PK and PD profiles showed a greater insulin concentration and effect when U-500R was administered via CSII compared to SC injection, primarily due to basal insulin infusion for CSII. The ratio of geometric least squares AUC0-tlast means SC:CSII (90% CI) is 0.857 (0.729, 1.01) with correction (mean AUC0-tlast: 5230 pmol*L/h [SC injection] and 6070 pmol*L/h [CSII, with correction]) and 0.424 (0.361, 0.499) without correction (mean AUC0-tlast: 12300 pmol*L/h [CSII, without correction]). Median time-to-peak insulin concentration was six hours (range 0.5-8 hours) via SC injection and five hours (0.5-12 hours) via CSII. CONCLUSIONS: In adults with T2D on high-dose insulin, U-500R PK/PD parameters were similar for a 100-unit bolus when given by SC injection or CSII via a U-500R pump.

Understanding concentrated insulins: a systematic review of randomized controlled trials.

OBJECTIVE: To compile, analyze, and summarize the literature on concentrated insulins (i.e. concentrations >100 units/mL) from randomized controlled trials and derive guidance on appropriate use of these agents. METHODS: Searches were conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, Trialtrove (through April 2016) and ClinicalTrials.gov (through April 2017) for phase 1-4 clinical studies using concentrated insulins. Selected studies included multiple-arm, randomized controlled trials evaluating subcutaneously administered concentrated insulins. Trial registration numbers (selected studies) were searched in Medline, Embase and Google Scholar (through April 2017). Late-phase studies were graded using guidance from the Agency for Healthcare Research and Quality. RESULTS: Thirty-eight completed trials (7900 participants) and 34 qualifying publications were identified. Four marketed concentrated insulins were evaluated: two long-acting basal (insulin glargine 300 units/mL and insulin degludec 200 units/mL [IDeg200]), one rapid-acting prandial (insulin lispro 200 units/mL [ILis200]), and one prandial/basal (human regular insulin 500 units/mL). Early-phase trials established bioequivalence for IDeg200 and ILis200 with the corresponding 100 units/mL formulations. Efficacy studies showed noninferior glycemic control between comparators for long-acting basal and prandial/basal products with generally low severe hypoglycemia. Six additional concentrated insulins with completed early-phase development were also identified. CONCLUSION: Concentrated-insulin products demonstrated efficacious and safe outcomes in appropriate patients. Clinical findings (HbA1c and hypoglycemia) and methodology (initiation and titration), patient factors (insulin experience and dosing requirements) and treatment characteristics (bioequivalence, potency and device features) are important considerations. This overview of these and other factors provides essential information and guidance for using concentrated insulins in clinical practice.

Translating U-500R Randomized Clinical Trial Evidence to the Practice Setting: A Diabetes Educator/Expert Prescriber Team Approach.

Purpose The purpose of this article is to provide recommendations to the diabetes educator/expert prescriber team for the use of human regular U-500 insulin (U-500R) in patients with severely insulin-resistant type 2 diabetes, including its initiation and titration, by utilizing dosing charts and teaching materials translated from a recent U-500R clinical trial. Conclusions Clinically relevant recommendations and teaching materials for the optimal use and management of U-500R in clinical practice are provided based on the efficacy and safety results of and lessons learned from the U-500R clinical trial by Hood et al, current standards of practice, and the authors' clinical expertise. This trial was the first robustly powered, randomized, titration-to-target trial to compare twice-daily and three-times-daily U-500R dosing regimens. Modifications were made to the initiation and titration dosing algorithms used in this trial to simplify dosing strategies for the clinical setting and align with current glycemic targets recommended by the American Diabetes Association. Leveraging the expertise, resources, and patient interactions of the diabetes educator who can provide diabetes self-management education and support in collaboration with the multidisciplinary diabetes team is strongly recommended to ensure patients treated with U-500R receive the timely and comprehensive care required to safely and effectively use this highly concentrated insulin.

Initiation of human regular U-500 insulin use is associated with improved glycemic control: a real-world US cohort study.

AIM: Describe the characteristics of patients initiating human regular U-500 insulin (U-500R) and their subsequent glycemic control in a real-world setting. METHODS: US Humedica electronic health record system data (July 2007-September 2011) were used to identify patients with diabetes aged ≥18 years with ≥1 records for U-500R prescriptions, 6 months of preindex data, 12 months following first use of U-500R, and at least one glycated hemoglobin (HbA1c) value in both preindex and postindex periods. Paired t tests were used to measure the change in HbA1c from preindex to postindex periods (last or most recent values) and hypoglycemia. RESULTS: Among patients initiating U-500R (N=445), 96.9% had type 2 diabetes with mean age 57 years and mean body mass index 40.4 kg/m(2). Postindex prescriptions were written for U-500R alone (47.0%, group A) and concomitant U-500R/U-100 insulins (53.0%, group B). Concomitant oral antihyperglycemic agents (AHAs) and non-insulin injectable AHAs were used by 43.4% and 14.6% of patients, respectively. Following initiation of U-500R, mean HbA1c improved 0.68% in all patients (p<0.0001 compared with baseline), but the decrease in HbA1c did not differ significantly between groups (A: 0.78%; B: 0.60%). Overall, hypoglycemic events, largely captured in the outpatient setting, increased in incidence from 6.7% to 11.9% (p≤0.0001) and from 0.23 to 0.39 events/patient/year, an increase of 0.16 (p=0.003), from preindex to postindex. CONCLUSIONS: This real-world outcomes analysis demonstrates that U-500R initiation is associated with a clinically meaningful improvement in glycemic control over the subsequent 12-month period with modest increase in incidence and rate of hypoglycemia.

Practice tips and tools for the successful use of U-500 regular human insulin: the diabetes educator is key.

This review provides information to equip diabetes educators to instruct and guide patients in using U-500 human regular insulin (U-500R). The article includes an overview of U-500R pharmacology and clinical data, strategies for outpatient and inpatient use, and tools for patient education. U-500R is useful for treating patients with any type of diabetes who require high doses of insulin. U-500R alleviates the volume-related problems associated with high doses of U-100 insulin, making treatment with high doses of insulin more feasible (because of the need for fewer injections for patients) as well as more cost-efficient and potentially more effective. These tools can help diabetes educators feel more comfortable and confident as they advise and educate patients who receive high-dose U-500R as part of their overall diabetes care plan. The diabetes educator plays a vital role in helping patients use U-500R safely and successfully.

Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin.

Pharmacokinetic/pharmacodynamic (PK/PD) studies of human regular U-500 insulin (U-500R) at high doses commonly used in clinical practice (>100 units) have not been performed. The current analysis applied PK/PD modeling/simulation to fit the data and simulate single-dose and steady-state PK/PD of U-500R high-dose regimens. Data from 3 single-dose euglycemic clamp studies in healthy obese and normal-weight patients, and normal-weight patients with type 1 diabetes were used to build the model. The model was sequential (PK inputs fed into PD component). PK was described using a 1-compartment model with first-order absorption and elimination. The model estimated separate absorption rate constants for U-500R and human regular U-100 insulin. The PD component used an effect compartment model, parameterized in terms of maximum pharmacologic effect (E(max)) and concentration to achieve 50% of E(max). The model described the data well. Steady-state PK for once-daily (QD), twice-daily (BID), or thrice-daily (TID) administration appeared to be reached 24 hours after the first dose. At steady-state, QD dosing showed the greatest fluctuations in PK/PD. BID dosing showed a gradual increase in insulin action with each dose and a fairly stable basal insulin effect. For TID dosing, activity was maintained throughout the dosing interval. PK/PD modeling/simulation of high U-500R doses supports BID or TID administration with an extended duration of activity relative to QD. TID dosing may provide slightly better full-day insulin effect. Additional PK/PD studies and randomized controlled trials of U-500R are needed to validate model predictions in patients with insulin-resistant diabetes requiring high-dose insulin.

Cost, healthcare resource utilization, and adherence of individuals with diabetes using U-500 or U-100 insulin: a retrospective database analysis.

OBJECTIVE: To describe costs, healthcare resource utilization, and adherence of US patients receiving human regular U-500 insulin (U-500R), compared to patients receiving high-dose (>200 units/day) U-100 insulins (U-100) by subcutaneous injection for the treatment of diabetes. METHODS: A retrospective analysis of data from Thomson Reuters MarketScan Research Databases (7/1/2008 to 12/31/2010). Difference-in-differences analyses were conducted on cost (medical, pharmacy, and overall costs) and on healthcare resource utilization variables (overall, diabetes-related, and non-diabetes-related medical visits). Adherence rates to the index insulins were assessed by proportion of days covered (PDC). RESULTS: Seven hundred and eleven (19%) patients in the U-500R cohort and 1508 (6%) patients in the U-100 cohort met selection criteria. Propensity score matching resulted in 684 matched pairs. Mean change in annualized pharmacy costs was in favor of the U-500R vs the U-100 cohort (-$1258 vs $3345, a difference of -$4603, p < 0.0001). Mean overall cost increase in the U-500R vs the U-100 cohort was also lower ($1999 vs $9104, a difference of -$7105, p = 0.005). The proportion of patients with at least one coded hypoglycemic event during the 12-month post-index period was higher in the U-500R vs the U-100 cohort (17.1% vs 11.7%, p < 0.005), but neither hypoglycemia rate (2.73 vs 2.90 events per person) nor hypoglycemia-specific costs (mean $1669 vs $1543) were significantly different. No significant differences were noted between cohorts for change (post-pre) in any resource utilization category. PDC was greater in the U-500R vs the U-100 cohort (65.2% vs 39.5%, p < 0.0001). LIMITATIONS: Claims data are not as accurate as empirical evaluation by a clinician. Glycemic control data were not available for this analysis. CONCLUSIONS: In patients requiring high-dose insulin, treatment with U-500R vs high-dose U-100 insulins is associated with significant decreases in pharmacy and overall costs, slightly higher hypoglycemia incidence, no difference in hypoglycemia-specific costs or in resource utilization, and better adherence.

Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects.

OBJECTIVE: Human regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL). RESEARCH DESIGN AND METHODS: This was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects. RESULTS: Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC(0-)(t)(')]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tR(max50), tR(last)) were prolonged for U-500R versus U-100R at both doses (P < 0.05). CONCLUSIONS: Overall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.

Use of concentrated insulin human regular (U-500) for patients with diabetes.

PURPOSE: The efficacy and safety of and key clinical considerations for using U-500 insulin human regular in the treatment of high-dose insulin-treated patients in a wide variety of settings are examined. SUMMARY: U-500 regular insulin has been available in the United States since 1952, but only recently has it become more commonly prescribed for patients requiring large amounts of insulin to improve their blood glucose control. This use coincides with the increasing rates of obesity and type 2 diabetes associated with significant insulin resistance, which can necessitate the need for doses of insulin exceeding 200 units/day. However, many health care professionals are relatively unfamiliar with this concentrated insulin formulation. U-500 regular insulin has a pharmacokinetic and pharmacodynamic profile that differs from U-100 human insulins and analogues. Although no randomized clinical trials using U-500 insulin have been performed, eight case series (involving 160 patients) have been published. Rare or infrequent occurrences of hypoglycemia with U-500 insulin have been reported. Of the medication errors associated with U-500 insulin, administration and dispensing errors occurred most frequently. With the increase in prescribing of U-500 insulin, pharmacists must be aware of the complex issues involved with appropriate prescribing, dispensing, and provision of patient education to maximize patient safety and avoid administration errors and dosing confusion. CONCLUSION: U-500 insulin is efficacious and safe for patients with type 2 diabetes who require a high dosage of insulin to control hyperglycemia. However, health care professionals should be well educated and vigilant about patient safety issues regarding the drug's prescription, dosing, and administration.

Direct costs associated with initiating NPH insulin versus glargine in patients with type 2 diabetes: a retrospective database analysis.

AIMS: To compare total costs and risk of hypoglycemia in patients with type 2 diabetes (T2D) initiated on NPH insulin versus glargine in a real-world setting. METHODS: This study used claims data (10/2001 to 06/2005) from a privately insured U.S. population of adult T2D patients who were initiated on NPH or glargine following a 6-month insulin-free period. A sample of 1698 glargine-treated and 400 NPH-treated patients met the inclusion criteria. Total and diabetes-related costs (inflation-adjusted to 2006) were calculated for 6-month pre- and post-index periods and compared between 400 patient pairs matched by a propensity score method. RESULTS: In the post-index 6-month period, glargine patients incurred higher diabetes-related drug costs than NPH patients ($785 versus $632, p<0.0001) but there were no significant differences in diabetes-related medical or total costs, or all other total cost categories. Compared to the pre-index period, glargine patient costs declined by $2420 (p=0.058) whereas NPH patient costs declined by $4200 (p=0.046), with no statistically significant group differences (p=0.469). Among patients with hypoglycemia-related claims (0.75% in both groups), mean hypoglycemia-related costs were $85 and $202 for NPH and glargine patients, respectively (p=0.564). CONCLUSION: Initiation of either NPH or glargine was associated with major cost reductions and infrequent hypoglycemia-related claims.

Impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens: a post hoc analysis of clinical trials in type 2 diabetes mellitus.

OBJECTIVE: To explore the impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens in patients with type 2 diabetes mellitus. METHODS: In this post hoc analysis, pooled data from 11 multinational clinical trials involving 1455 patients with type 2 diabetes were used to compare specific insulin treatments in Latino/Hispanic, Asian, African-descent, and Caucasian patients. Insulin treatments included once daily insulin glargine or neutral protamine Hagedorn (BASAL), insulin lispro mix 75/25 twice daily (LMBID), or insulin lispro mix 50/50 three times daily (LMTID). RESULTS: Race/ethnicity was associated with significant outcome differences for each of the insulin regimens. BASAL therapy was associated with greater improvement in several measures of glycemic control among Latino/Hispanic patients compared with Caucasian patients (lower end point hemoglobin A1c, greater reduction in hemoglobin A1c from baseline, and a larger proportion of patients achieving hemoglobin A1c level <7%). In contrast, LMBID therapy was associated with higher end point hemoglobin A1c and a smaller decrease in hemoglobin A1c from baseline in Latino/Hispanic and Asian patients than in Caucasian patients. Furthermore, fewer Asian patients attained a hemoglobin A1c level <7% than did Caucasians patients. For LMTID therapy, hemoglobin A1c outcomes were comparable across patient groups. Fasting blood glucose and glycemic excursions varied among racial/ethnic groups for the 3 insulin regimens. Weight change was comparable among racial/ethnic groups in each insulin regimen. During treatment with LMTID, Asian patients experienced higher incidence and rate of severe hypoglycemia than Caucasian patients. CONCLUSIONS: Latino/Hispanic, Asian, and African-descent patients with type 2 diabetes show different metabolic responses to insulin therapy, dependent in part on insulin type and regimen intensity.

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.