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.

Human regular U-500 insulin via continuous subcutaneous insulin infusion versus multiple daily injections in adults with type 2 diabetes: The VIVID study.

AIM: To compare the safety and efficacy of U500-R delivered by a novel, specifically designed U500-R insulin pump with U-500R delivered by multiple daily injections (MDI). METHODS: The phase 3 VIVID study randomized people with type 2 diabetes to U-500R by continuous subcutaneous insulin infusion (CSII) or MDI. Participants (aged 18-85 years) had HbA1c ≥7.5% and ≤12.0% and a total daily dose of insulin >200 and ≤600 U/day. After a 2-week transition to three times daily injections of U-500R, participants were treated for 24 weeks with U-500R by CSII or MDI. Treatment arms were compared using mixed model repeated measures analysis. RESULTS: The study randomized 420 participants (CSII: 209, MDI: 211) with 365 completers. Mean changes from baseline were: HbA1c, -1.27% (-13.9 mmol/mol) with CSII and -0.85% (-9.3 mmol/mol) with MDI (difference - 0.42% [-4.6 mmol/mol], P <0.001); fasting plasma glucose, -33.9 mg/dL (-1.9 mmol/L) with CSII and 1.7 mg/dL (0.09 mmol/L) with MDI (difference - 35.6 mg/dL [-2.0 mmol/L], P <0.001); total daily dose, 2.8 U with CSII and 51.3 U with MDI (P < 0.001). Weight changes and rates of documented symptomatic and severe hypoglycaemia were similar between groups; the CSII group had a higher rate of nocturnal hypoglycaemia. CONCLUSIONS: In type 2 diabetes requiring high doses of insulin, both methods of U-500R delivery lowered HbA1c. However, the CSII group attained greater HbA1c reduction with significantly less insulin. Individualized dose titration will be important to balance glycaemic control with hypoglycaemia risk.

Lilly Insulin Glargine Versus Lantus® in Insulin-Naïve and Insulin-Treated Adults with Type 2 Diabetes: A Randomized, Controlled Trial (ELEMENT 5).

INTRODUCTION: This study compared the efficacy and safety of similar U-100 insulin glargine products, namely, Lilly insulin glargine (LY IGlar; Basaglar®) and the reference insulin glargine product (IGlar; Lantus®), used once daily in combination with oral antihyperglycemic medications (OAMs) in adults with type 2 diabetes (T2D). METHODS: ELEMENT 5 was a phase III, randomized, multinational, open-label, treat-to-target, 24-week trial. Participants were insulin naïve (glycated hemoglobin [HbA1c] ≥ 7.0% to ≤ 11.0%) or on basal insulin (IGlar, neutral protamine Hagedorn or insulin detemir; HbA1c ≤ 11.0%) and taking ≥ 2 OAMs. The primary objective was to show  that LY IGlar is noninferior to IGlar in terms of HbA1c reduction (0.4% noninferiority margin). RESULTS: The study population (N = 493) was predominantly Asian (48%) or White (46%), with similar baseline characteristics between arms (P > 0.05). At 24 weeks, LY IGlar was noninferior to IGlar in terms of change in HbA1c level from baseline (- 1.25 vs. - 1.22%, respectively; least squares mean difference - 0.04%; 95% confidence interval - 0.22%, 0.15%). Other 24-week efficacy and safety results were also similar between treatments (P > 0.05), including insulin dose; percentage of patients having HbA1c of < 7% and ≤ 6.5%; overall rate and incidence of total, nocturnal, and severe hypoglycemia; adverse events; insulin antibody response; and weight gain. Daily mean 7-point self-monitored blood glucose reduction was similar between treatments at 24 weeks, with no differences at any time point except premorning-meal (fasting) blood glucose (LY IGlar - 2.37 mmol/L; IGlar - 2.69 mmol/L; P = 0.007). CONCLUSION: Overall, LY IGlar and IGlar combined with OAMs provided similar glucose control and safety findings in this T2D population, which included a greater proportion of Asian patients and had broader background basal insulin experience than a previously studied T2D population. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02302716. FUNDING: Eli Lilly and Company and Boehringer Ingelheim. Plain language summary available for this article.

Similar Intrapatient Blood Glucose Variability with LY2963016 and Lantus® Insulin Glargine in Patients with Type 1 (T1D) or Type 2 Diabetes, Including a Japanese T1D Subpopulation.

INTRODUCTION: LY2963016 insulin glargine (LY IGlar) and Lantus® (IGlar), both with identical primary amino acid sequences, were compared in two phase 3 studies for intrapatient blood glucose variability. METHODS: ELEMENT-1 was a 52-week study in patients with type 1 diabetes (T1D), which included Japanese patients, and ELEMENT-2 was a 24-week study in non-Japanese patients with type 2 diabetes (T2D). In ELEMENT-1, 535 patients with T1D were evaluable (268 LY IGlar and 267 IGlar). Of these, 100 were Japanese patients (49 LY IGlar and 51 IGlar). In ELEMENT-2, 756 patients with T2D were evaluable (376 LY IGlar and 380 IGlar). We evaluated and compared intrapatient blood glucose variability of LY IGlar and IGlar in these studies from three different perspectives: intrapatient between-day fasting blood glucose variability, intrapatient between-day daily mean blood glucose variability, and intrapatient within-day blood glucose variability. RESULTS: Overall, evaluations of all three indices showed that intrapatient blood glucose variability was similar between LY IGlar and IGlar throughout the study periods both in the overall populations of patients with T1D and T2D and also in the subgroup of Japanese patients with T1D. CONCLUSION: Intrapatient blood glucose variability between LY IGlar and IGlar was shown to be similar in patients with T1D or T2D. CLINICAL TRIAL REGISTRATION: NCT01421147 (ELEMENT-1) and NCT01421459 (ELEMENT-2). FUNDING: Eli Lilly and Company (Indianapolis, IN, USA); Boehringer-Ingelheim (Ridgefield, CT, USA); Eli Lilly Japan K.K. (Kobe, Japan) and Nippon Boehringer Ingelheim Co., Ltd. (Tokyo, Japan).

Similar Efficacy and Safety of Basaglar® and Lantus® in Patients with Type 2 Diabetes in Age Groups (< 65 Years, ≥ 65 Years): A Post Hoc Analysis from the ELEMENT-2 Study.

INTRODUCTION: To compare efficacy and safety of Basaglar® [insulin glargine 100 units/mL; LY insulin glargine (LY IGlar)] to Lantus® [insulin glargine 100 units/mL; SA insulin glargine (SA IGlar)] in older (≥ 65 years) or younger (< 65 years) patients with type 2 diabetes (T2D). METHODS: This subgroup analysis of a phase 3, randomized, double-blind, multinational, 24-week study compared LY IGlar and SA IGlar on several clinical efficacy (change in glycated hemoglobin (A1c), basal insulin dose, weight) and safety outcomes (incidence of adverse events, insulin antibodies, hypoglycemia incidence and rates) in patients either ≥ 65 or < 65 years. RESULTS: Compared with patients aged < 65 years (N = 542), patients aged ≥ 65 years (N = 214) had a significantly longer duration of diabetes; lower baseline A1c and body weight; and body mass index; and were more likely to report prestudy SA IGlar use. Compared to patients < 65 years, patients ≥ 65 years needed a lower basal insulin dose and experienced lower body weight gain. There were no significant treatment-by-age interactions for the clinical efficacy and safety outcomes, indicating that there was no differential treatment effect (LY IGlar vs SA IGlar) for patients ≥ 65 years vs those < 65 years. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes. CONCLUSIONS: LY IGlar and SA IGlar exhibit similar efficacy and safety in patients with T2D who are ≥ 65 years and in those < 65 years. TRIAL REGISTRATION: ClinicalTrials.gov trial registration: NCT01421459. FUNDING: Eli Lilly and Company and Boehringer-Ingelheim.

Plain language summary available for this article.The aim of this phase 3 clinical study was to compare the efficacy and safety of two drugs, Basaglar^® (LY IGlar) and Lantus (SA IGlar), in patients with type 2 diabetes that were either 65 years of age and/or older or younger than 65 years of age. This study ran for 24 weeks. The factors used to measure efficacy were changes in glycated hemoglobin (A1c), insulin dose, and weight. The safety outcomes were incidence of adverse events, incidence and levels of insulin antibodies, and the incidence and rate of low blood sugar. Compared with patients less than 65 years of age (N = 542), patients 65 years of age and older (N = 214) had diabetes for a significantly longer time period; had a lower baseline A1c, body weight, and body mass index; and were more likely to report that they used SA IGlar prestudy. Compared to patients less than 65 years of age, patients equal to or older than 65 years of age showed significantly smaller increases in insulin dose and body weight. There were no significant treatment-by-age interactions for the efficacy and safety outcomes, indicating that there was no difference in treatment effect (LY IGlar vs SA IGlar) for patients equal to or older than 65 years of age vs those less than 65 years of age. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes. LY IGlar and SA IGlar have similar efficacy and safety in patients with T2D who are equal to or older than 65 years of age and in those less than 65 years of age.

Clinical Outcomes of Patients with Diabetes Who Exhibit Upper-Quartile Insulin Antibody Responses After Treatment with LY2963016 or Lantus® Insulin Glargine.

INTRODUCTION: We compared insulin antibody response (IAR) profiles in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who received LY2963016 insulin glargine (LY IGlar) or Lantus® insulin glargine (IGlar) and evaluated the potential relationship between higher IARs and clinical and safety outcomes with a focus on patients who exhibited antibody responses in the upper quartile. METHODS: Data from ELEMENT-1 (52-week open-label in T1D) and ELEMENT-2 (24-week, double-blind study in T2D) were analyzed. Maximum postbaseline IAR levels and proportions of patients in the upper quartile of maximum antibody percent binding (UQMAPB; patients with maximum postbaseline percent binding in the highest 25% of maximum values observed) were compared for differential treatment effects on clinical efficacy outcomes and incidence of adverse events. Continuous outcomes were analyzed by analysis of covariance. Categorical data were analyzed by the Cochran-Mantel-Haenszel or Breslow-Day test. RESULTS: In both studies (N = 532 evaluable patients with T1D; N = 730 with T2D), no statistically significant differences between LY IGlar and IGlar were observed for maximum antibody percent binding (MAPB) levels or for proportions of patients in the respective UQMAPB. No statistically significant differential treatment effects were observed in the relationship between MAPB and clinical efficacy and safety outcomes. CONCLUSIONS: Maximum postbaseline IAR levels and the proportion of patients with high IAR levels were similar for LY IGlar and IGlar. High antibody levels did not affect clinical outcomes. These results add further evidence supporting similar IARs of LY IGlar and IGlar. FUNDING: Eli Lilly and Company and Boehringer-Ingelheim.

Prandial premixed insulin analogue regimens versus basal insulin analogue regimens in the management of type 2 diabetes: an evidence-based comparison.

BACKGROUND: Insulin is an effective treatment for type 2 diabetes (T2D), a progressive condition in which insulin deficiency is one of the core defects. When patients with T2D are unable to achieve glycemic goals with diet and oral antihyperglycemic medications, a common starting insulin regimen consists of basal or premixed insulin added to oral antihyperglycemic medications. When glycemic goals are not achieved with the initial insulin regimen, a basal-bolus regimen is necessary. OBJECTIVE: This article reviews clinical-trial data on the efficacy and safety profile of prandial premixed insulin analogues (insulin aspart and insulin lispro) compared with basal insulin analogues (insulin glargine, insulin detemir, and insulin lispro protamine suspension), with or without a prandial insulin analogue, in the management of T2D. METHODS: A systematic search of Ovid, MEDLINE, and EMBASE (1995-2007) was performed to identify published randomized controlled trials comparing prandial premixed insulin analogues with basal insulin analogues, with or without prandial insulin, in patients with T2D. The search terms were premixed insulin analogues, premixed insulin, biphasic insulin aspart, insulin aspart 70/30, insulin aspart 50/50, premixed insulin lispro, insulin lispro 75/25, insulin lispro 50/50, glargine, and detemir. Abstracts presented at the 2005 and 2006 meetings of the American Diabetes Association and the European Association for the Study of Diabetes and bibliographies of the identified studies were also reviewed. Predetermined criteria for study inclusion were treatment duration of at least 12 weeks, T2D diagnosed using valid criteria, use of a basal insulin analogue (with or without rapid-acting insulin) as a study comparator, and use of well-accepted end points (eg, glycosylated hemoglobin [HbA1c], hypoglycemia, preprandial and postprandial blood glucose). RESULTS: Of the identified randomized controlled trials, 3 studies compared premixed insulin analogues containing 70% or 75% basal and 30% or 25% rapid-acting insulin analogue with basal insulin analogues only, and 3 studies evaluated premixed insulin analogues containing 50% basal and 50% rapid-acting insulin analogue with basal insulin analogues only. Use of prandial premixed insulin analogues was associated with better overall and postprandial glycemic control. In the studies that compared twice-daily premixed insulin analogues with a basal insulin analogue, changes in HbA1c ranged from -1.00% to -2.79% and from -0.42% to -2.36%, respectively (P < 0.01). In the studies that compared thrice-daily premixed insulin analogues with a basal insulin analogue, changes in HbA1c ranged from -0.72% to -1.2% and from -0.3% to -0.75%, respectively (P < 0.01). These results were achieved with some increase in overall hypoglycemia, but not in nocturnal or severe hypoglycemia. Doses of the premixed insulin analogues were adjusted during the titration period to achieve glycemic goals. CONCLUSIONS: The results of this systematic review suggest that regimens consisting of prandial premixed insulin analogues, which provide both basal and prandial insulin coverage, may be used as an initial insulin regimen in patients with T2D to enable better overall, preprandial, and postprandial glycemic control compared with a basal insulin analogue regimen alone. Premixed insulin analogues are an effective option for initiating and intensifying insulin therapy in patients with T2D.

Prandial premixed insulin analogue regimens versus basal insulin analogue regimens in the management of type 2 diabetes: an evidence-based comparison.

BACKGROUND: Insulin is an effective treatment for type 2 diabetes (T2D), a progressive condition in which insulin deficiency is one of the core defects. When patients with T2D are unable to achieve glycemic goals with diet and oral antihyperglycemic medications, a common starting insulin regimen consists of basal or premixed insulin added to oral antihyperglycemic medications. When glycemic goals are not achieved with the initial insulin regimen, a basal-bolus regimen is necessary. OBJECTIVE: This article reviews clinical-trial data on the efficacy and safety profile of prandial premixed insulin analogues (insulin aspart and insulin lispro) compared with basal insulin analogues (insulin glargine, insulin detemir, and insulin lispro protamine suspension), with or without a prandial insulin analogue, in the management of T2D. METHODS: A systematic search of Ovid, MEDLINE, and EMBASE (1995-2007) was performed to identify published randomized controlled trials comparing prandial premixed insulin analogues with basal insulin analogues, with or without prandial insulin, in patients with T2D. The search terms were premixed insulin analogues, premixed insulin, biphasic insulin aspart, insulin aspart 70/30, insulin aspart 50/50, premixed insulin lispro, insulin lispro 75/25, insulin lispro 50/50, glargine, and detemir. Abstracts presented at the 2005 and 2006 meetings of the American Diabetes Association and the European Association for the Study of Diabetes and bibliographies of the identified studies were also reviewed. Predetermined criteria for study inclusion were treatment duration of at least 12 weeks, T2D diagnosed using valid criteria, use of a basal insulin analogue (with or without rapid-acting insulin) as a study comparator, and use of well-accepted end points (eg, glycosylated hemoglobin [HbA(1c)], hypoglycemia, preprandial and postprandial blood glucose). RESULTS: Of the identified randomized controlled trials, 3 studies compared premixed insulin analogues containing 70% or 75% basal and 30% or 25% rapid-acting insulin analogue with basal insulin analogues only, and 3 studies evaluated premixed insulin analogues containing 50% basal and 50% rapid-acting insulin analogue with basal insulin analogues only. Use of prandial premixed insulin analogues was associated with better overall and postprandial glycemic control. In the studies that compared twice-daily premixed insulin analogues with a basal insulin analogue, changes in HbA(1c) ranged from -1.00% to -2.79% and from -0.42% to -2.36%, respectively (P < 0.01). In the studies that compared thrice-daily premixed insulin analogues with a basal insulin analogue, changes in HbA(1c) ranged from -0.72% to -1.2% and from -0.3% to -0.75%, respectively (P < 0.01). These results were achieved with some increase in overall hypoglycemia, but not in nocturnal or severe hypoglycemia. Doses of the premixed insulin analogues were adjusted during the titration period to achieve glycemic goals. CONCLUSIONS: The results of this systematic review suggest that regimens consisting of prandial premixed insulin analogues, which provide both basal and prandial insulin coverage, may be used as an initial insulin regimen in patients with T2D to enable better overall, preprandial, and postprandial glycemic control compared with a basal insulin analogue regimen alone. Premixed insulin analogues are an effective option for initiating and intensifying insulin therapy in patients with T2D.

A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes.

OBJECTIVE: To compare the efficacy and safety of continuous subcutaneous insulin infusion (CSII) and multiple daily injection (MDI) in older adults with insulin-treated type 2 diabetes and to assess treatment satisfaction and quality of life. RESEARCH DESIGN AND METHODS: Adults (n = 107) > or =60 years of age (mean age 66 years) with insulin-treated type 2 diabetes (mean duration 16 years, BMI 32 kg/m(2), and HbA(1C) [A1C] 8.2%) were randomized to CSII (using insulin lispro) or MDI (using insulin lispro and insulin glargine) in a two-center, 12-month, prospective, randomized, controlled clinical trial. Efficacy was assessed with A1C, safety by frequency of hypoglycemia, and treatment satisfaction and quality of life with the Diabetes Quality of Life Clinical Trial Questionnaire and the 36-item short-form health survey, version 2. RESULTS: Forty-eight CSII subjects (91%) and 50 MDI subjects (93%) completed the study. Mean A1C fell by 1.7 +/- 1.0% in the CSII group to 6.6% and by 1.6 +/- 1.2% in the MDI group to 6.4%. The difference in A1C between treatment groups was not statistically significant (P = 0.20). Eighty-one percent of CSII subjects and 90% of MDI subjects experienced at least one episode of minor (self-treated) hypoglycemia (P = 0.17), and three CSII and six MDI subjects experienced severe hypoglycemia (P = 0.49). Rates of severe hypoglycemia were similarly low in the two groups (CSII 0.08 and MDI 0.23 events per person-year, P = 0.61). Weight gain did not differ between groups (P = 0.70). Treatment satisfaction improved significantly with both CSII and MDI (P < 0.0001), and the difference between groups was not statistically significant (P = 0.58). CONCLUSIONS: In older subjects with insulin-treated type 2 diabetes, both CSII and MDI achieved excellent glycemic control with good safety and patient satisfaction.

Impact of a critical pathway on inpatient management of diabetic ketoacidosis.

To assess the management of diabetic ketoacidosis (DKA) and evaluate if introduction of a critical pathway improves management, we studied adults admitted with DKA to the Medicine and Critical Care Services in a US teaching hospital. Patients admitted with DKA in 1997 before implementation of the critical pathway were the control group (n=72). In 1998, housestaff and nurses in the emergency department (ED) and on the General Medicine and Critical Care Services were instructed in the use of the critical pathway. Patients admitted with DKA during 1998 (n=77) were the intervention group. Length of stay (LOS), hospital cost, adherence to guidelines, and medical outcomes to be avoided were compared, and regression analyses were performed to correlate processes and outcomes of care. Mean LOS and variability in LOS decreased during the intervention period, especially in patients treated without endocrinology consultation (EC) (5.2 +/- 10.6 vs. 2.4 +/- 2.1 days, P=0.01), and hospital cost and variability in cost tended to decrease ($6441 +/- 15,204 vs. $3625 +/- 3478, P=0.24). More intervention subjects received the recommended intravenous fluid volume (88 vs. 71%, P=0.013), education in sick-day management (77 vs. 54%, P=0.006), and EC (38 vs. 21%, P=0.03). Insulin management was not changed. We conclude that implementation of a DKA critical pathway reduced practice variation and was associated with shorter LOS and a trend toward decreased cost. Some processes of care were improved but many require additional interventions.

Improving diabetes processes of care in managed care.

OBJECTIVE: To evaluate the impact of systematic patient evaluation and patient and provider feedback on the processes and intermediate outcomes of diabetes care in Independent Practice Association model internal medicine practices. RESEARCH DESIGN AND METHODS: Nine practices providing care to managed care patients were randomly assigned as intervention or comparison sites. Intervention-site subjects had Annual Diabetes Assessment Program (ADAP) assessments (HbA(1c), blood pressure, lipids, smoking, retinal photos, urine microalbumin, and foot examination) at years 1 and 2. Comparison-site subjects had ADAP assessments at year 2. At Intervention sites, year 1 ADAP results were reviewed with subjects, mailed to providers, and incorporated into electronic medical records with guideline-generated suggestions for treatment and follow-up. Medical records were evaluated for both groups for the year before both the year 1 and year 2 ADAP assessments. Processes and intermediate outcomes were compared using linear and logistic mixed hierarchical models. RESULTS: Of 284 eligible subjects, 103 of 173 (60%) at the Intervention sites and 71 of 111 (64%) at the comparison sites participated; 83 of 103 (81%) of the intervention-site subjects returned for follow-up at year 2. Performance of the six recommended assessments improved in intervention-site subjects at year 2 compared with year 1 (5.8 vs. 4.3, P = 0.0001) and compared with comparison-site subjects at year 2 (4.2, P = 0.014). No significant changes were noted in intermediate outcomes. CONCLUSIONS: The ADAP significantly improved processes of care but not intermediate outcomes. Additional interventions are needed to improve intermediate outcomes.