Reduced nocturnal hypoglycaemia with basal insulin peglispro compared with insulin glargine: pooled analyses of five randomized controlled trials.

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action, resulting from reduced peripheral effects. This report summarizes hypoglycaemia data from five BIL phase III studies with insulin glargine as the comparator, including three double-blind trials. Prespecified pooled analyses (n = 4927) included: patients with type 2 diabetes (T2D) receiving basal insulin only, those with T2D on basal-bolus therapy, and those with type 1 diabetes (T1D). BIL treatment resulted in a 36-45% lower nocturnal hypoglycaemia rate compared with glargine, despite greater reduction in glycated haemoglobin (HbA1c) and higher basal insulin dosing. The total hypoglycaemia rate was similar in patients with T2D on basal treatment only, trended towards being higher (10%) in patients with T2D on basal-bolus treatment (p = .053), and was 15% higher (p < .001) with BIL versus glargine in patients with T1D, with more daytime hypoglycaemia in the T1D and T2D groups who were receiving basal-bolus therapy. In T1D, during the maintenance treatment period (26-52 weeks), the total hypoglycaemia rate was not significantly different. There were no differences in severe hypoglycaemia in the T1D or T2D pooled analyses. BIL versus glargine treatment resulted in greater HbA1c reduction with less nocturnal hypoglycaemia in all patient populations, higher daytime hypoglycaemia with basal-bolus therapy in the T1D and T2D groups, and an associated increase in total hypoglycaemia in the patients with T1D.

Relationship of apolipoprotein A5 and apolipoprotein C3 levels to serum triglycerides in patients with type 2 diabetes.

BACKGROUND: The role of apolipoprotein A5 (ApoA5) in modulating triglyceride levels in humans is incompletely understood. Some researchers have reported modest positive correlations of ApoA5 with triglycerides while others have reported negative correlations. A recent report suggested that ApoA5 gene expression may be influenced by insulin. In type 2 diabetes, some groups have reported higher levels of ApoA5 compared to normals while others have reported lower levels. METHODS: To better understand the relationships between ApoA5, apolipoprotein C3 (ApoC3), and triglycerides in type 2 diabetes, ApoA5 levels were measured and correlated with triglyceride, insulin, and HbA1c levels. ApoC3 levels were measured and correlated with triglycerides. RESULTS: In patients with type 2 diabetes, ApoA5 levels were elevated compared to normals, with several patients having markedly increased levels confirmed by Western blotting. ApoA5 levels were positively correlated with triglycerides (r=0.60) but were not correlated with either HbA1c or serum insulin levels. ApoC3 levels were highly positively correlated with triglycerides (r=0.88). CONCLUSIONS: These data indicate that in patients with type 2 diabetes ApoA5 levels are positively correlated with triglycerides but are not correlated with HbA1c or insulin levels. ApoC3 levels are strongly positively correlated with triglycerides in these patients.

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.

Lack of effect of sucralose on glucose homeostasis in subjects with type 2 diabetes.

OBJECTIVE: To investigate the effect of 3-months' daily administration of high doses of sucralose, a non-nutritive sweetener, on glycemic control in subjects with type 2 diabetes. DESIGN: A multicenter, double-blind, placebo-controlled, randomized study, consisting of a 6-week screening phase, a 13-week test phase, and a 4-week follow-up phase. SUBJECTS/SETTING: Subjects with type 2 diabetes (age range 31 to 70 years) entered the test phase of this study; 128 subjects completed the study. The subjects were recruited from 5 medical centers across the United States and were, on average, obese. INTERVENTION: Subjects were randomly assigned to receive either placebo (cellulose) capsules (n=69) or 667 mg encapsulated sucralose (n=67) daily for the 13-week test phase. All subjects blindly received placebo capsules during the last 4 weeks of the screening phase and for the entire 4-week follow-up phase. MAIN OUTCOME MEASURES: Glycated hemoglobin (HbA1c), fasting plasma glucose, and fasting serum C-peptide were measured approximately every 2 weeks to evaluate blood glucose homeostasis. Data were analyzed by analysis of variance using repeated measures. RESULTS: There were no significant differences between the sucralose and placebo groups in HbA1c, fasting plasma glucose, or fasting serum C-peptide changes from baseline. There were no clinically meaningful differences between the groups in any safety measure. CONCLUSIONS: This study demonstrated that, similar to cellulose, sucralose consumption for 3 months at doses of 7.5 mg/kg/day, which is approximately three times the estimated maximum intake, had no effect on glucose homeostasis in individuals with type 2 diabetes. Additionally, this study showed that sucralose was as well-tolerated by the study subjects as was the placebo.

Lower glucose variability and hypoglycemia measured by continuous glucose monitoring with novel long-acting insulin LY2605541 versus insulin glargine.

OBJECTIVE: To use continuous glucose monitoring (CGM) to evaluate the impact of the novel, long-acting basal insulin analog LY2605541 on hypoglycemia and glycemic variability in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Hypoglycemia and glucose variability were assessed with CGM of interstitial glucose (IG) in a subset of patients with type 2 diabetes from a phase II, randomized, open-label, parallel study of LY2605541 (n = 51) or insulin glargine (GL) (n = 25). CGM was conducted on 3 consecutive days (72-84 h) during the week before week 0, 6, and 12 study visits. RESULTS: Measured by CGM for 3 days prior to the 12-week visit, fewer LY2605541-treated patients experienced hypoglycemic events overall (50.0 vs. 78.3%, P = 0.036) and nocturnally (20.5 vs. 47.8%, P = 0.027) and spent less time with IG ≤70 mg/dL than GL-treated patients during the 24-h (25 ± 6 vs. 83 ± 16 min, P = 0.012) and nocturnal periods (11 ± 5 vs. 38 ± 13 min, P = 0.024). These observations were detected without associated differences in the average duration of individual hypoglycemic episodes (LY2605541 compared with GL 57.2 ± 5.4 vs. 69.9 ± 10.2 min per episode, P = NS). Additionally, LY2605541-treated patients had lower within-day glucose SD for both 24-h and nocturnal periods. CONCLUSIONS: By CGM, LY2605541 treatment compared with GL resulted in fewer patients with hypoglycemic events and less time in the hypoglycemic range and was not associated with protracted hypoglycemia.

Basal insulin peglispro demonstrates preferential hepatic versus peripheral action relative to insulin glargine in healthy subjects.

OBJECTIVE: We evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects. RESEARCH DESIGN AND METHODS: This was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m(2)/min) in a fourth period, targeted to achieve 50-100% suppression of EGP. D-[3-(3)H] glucose was infused to assess rates of glucose appearance and disappearance. RESULTS: Mean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses. CONCLUSIONS: The novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.

The effect of adjusting for baseline hypoglycemia when analyzing hypoglycemia data: a systematic analysis of 15 diabetes clinical trials.

BACKGROUND: Baseline hypoglycemia rates are generally not collected or included as a covariate in statistical models used for analyzing hypoglycemia data. The objective of the present study was to examine the effect of adjusting for baseline hypoglycemia on estimation efficiency and statistical power. SUBJECTS AND METHODS: A post hoc analysis of data from 15 insulin trials, including patients with type 1 diabetes mellitus (T1DM) (n=210), previously insulin-treated type 2 diabetes mellitus (T2DM) (n=1,511), or T2DM and previously insulin-naive (n=1,075). Hypoglycemic episodes were analyzed with a negative binomial regression model. RESULTS: Baseline nocturnal hypoglycemia rate was significantly correlated with post-baseline nocturnal hypoglycemia rate in previously insulin-treated patients with T1DM and T2DM (correlation range, 0.37-0.63; P<0.001). Adjusting for baseline hypoglycemia resulted in a reduction in the SE for negative binomial regression for previously insulin-treated patients with T1DM and T2DM (range, 2.2-11.8%) and increased statistical power. Modeling of lengthening the lead-in period increases the correlation between baseline and post-baseline hypoglycemia event rate and statistical power. CONCLUSIONS: Baseline hypoglycemia rate is significantly correlated with post-baseline hypoglycemia rate for patients with diabetes treated with insulin prior to randomization. The length of the lead-in period can impact correlations between baseline and post-baseline data, and adjustment for baseline hypoglycemia may improve the estimation efficiency for hypoglycemia data analyses in clinical trials.

Better glycemic control and weight loss with the novel long-acting basal insulin LY2605541 compared with insulin glargine in type 1 diabetes: a randomized, crossover study.

OBJECTIVE To compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes. RESEARCH DESIGN AND METHODS In this randomized, Phase 2, open-label, 2 × 2 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL. RESULTS LY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = -9.9 mg/dL [90% CI -14.6 to -5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02). CONCLUSIONS In type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses.

A randomized, controlled study of once-daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes.

OBJECTIVE: To evaluate whether LY2605541 results in lower fasting blood glucose (FBG) versus insulin glargine (GL). RESEARCH DESIGN AND METHODS: This 12-week, randomized, open-label, Phase 2 study enrolled patients with type 2 diabetes (hemoglobin A(1c) [A1C] ≤ 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily. Patients converted to morning insulin administration during lead-in were randomized 2:1 from GL (n = 248) or NPH insulin (n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the morning. RESULTS: At 12 weeks, FBG (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (-0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: -0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001). CONCLUSIONS: In patients with type 2 diabetes, LY2605541 and GL had comparable glucose control and total hypoglycemia rates, but LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.

Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein A5 in human serum.

BACKGROUND: Apolipoprotein A5 (ApoA5) originally gained attention as a regulator of serum triglyceride concentrations through transgenic mouse studies. Our group recently developed the first assay to quantify serum ApoA5 protein concentrations and demonstrated that they are increased by administration of a potent peroxisome proliferator-activated receptor-alpha agonist. METHODS: To better characterize the circulating ApoA5, the protein was purified from human serum, and a definitive N-terminal protein sequence was obtained. In light of previous observations that ApoA5 was present in VLDL and not LDL, plasma infranatant and intermediate-density lipoprotein (IDL) were analyzed for ApoA5. Because the mature protein contains a single unpaired cysteine, ApoA5 in human serum was immunoprecipitated, and its migration pattern was examined via Western blotting under reducing and nonreducing conditions to determine whether the protein circulates as a disulfide-linked homodimer or heterodimer. RESULTS: Definitive N-terminal protein sequences obtained from ApoA5 purified from human serum indicated that cleavage of the signal peptide occurs in vivo at the predicted site. We found ApoA5 in VLDL, HDL, and chylomicrons but not in LDL, IDL, or plasma infranatant. Under both reducing and nonreducing conditions, ApoA5 migrated mainly as a single band with a relative molecular mass (Mr) of approximately 39,000, indicating that the protein exists in serum as a monomer and not as a disulfide-linked homodimer or heterodimer. CONCLUSIONS: Our data help characterize ApoA5 by defining its lipoprotein particle distribution, by determining its N-terminal protein sequence, and by demonstrating that the mature protein circulates mainly as a monomer and not as a disulfide-linked homodimer or heterodimer.