Attenuated suppression of lipolysis explains the increases in triglyceride secretion and concentration associated with basal insulin peglispro relative to insulin glargine treatment in patients with type 1 diabetes.

AIMS: To test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very-low-density lipoprotein (VLDL)-TG secretion and lipid oxidation, and decreased TG adipose tissue deposition. METHODS: In this open-label, randomized, 2-period crossover study, 14 patients with type 1 diabetes received once-daily, individualized, stable BIL or GL doses for 3 weeks. Palmitate flux was assessed using [9,10-3 H]palmitate infusion. VLDL-TG secretion, clearance and oxidation rate were assessed using primed-constant infusion of ex vivo labelled [1-14 C]VLDL-TG, while VLDL-TG storage rate was assessed using [9,10-3 H]VLDL-TG bolus injection. RESULTS: The VLDL-TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than during GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means for VLDL-TG clearance and oxidation were 0.92 (95% confidence interval [CI] 0.72, 1.17) and 1.31 (95% CI 0.91, 1.90), respectively. The difference in LS means for VLDL-TG storage rate was -0.36 (95% CI -0.83, 0.12). CONCLUSIONS: BIL-treated patients had higher effective lipolysis, VLDL-TG secretion and VLDL-TG concentration compared with GL-treated patients, explaining the increased plasma TG concentrations reported previously. Data support attenuated effects of BIL on lipolysis, in addition to the recently described hepato-preferential glucodynamic effects.

Novel hepato-preferential basal insulin peglispro (BIL) does not differentially affect insulin sensitivity compared with insulin glargine in patients with type 1 and type 2 diabetes.

AIMS: Basal insulin peglispro (BIL) is a novel PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and reduced peripheral effects, which results in a hepato-preferential action. In Phase 3 trials, patients with T1DM treated with BIL had lower prandial insulin requirements, yet improved prandial glucose control, relative to insulin glargine (GL). We hypothesized that this may be because of an enhanced sensitivity to prandial insulin with BIL resulting from lower chronic peripheral insulin action. MATERIALS AND METHODS: Two open-label, randomized, 2-period crossover clinical studies were conducted in 28 patients with T1DM and 24 patients with T2DM. In each study period, patients received once-daily, individualized, stable, subcutaneous doses of BIL or GL for 5 weeks before a euglycaemic 2-step hyperinsulinemic clamp procedure (with [6,6- 2 H2 ]-glucose in 12 of the patients with T1DM). M-values were derived from the clamp procedure for all patients, with rate of glucose appearance (Ra) and disappearance (Rd) and insulin sensitivity index (SI) determined from the clamps with [6,6- 2 H2 ]-glucose. RESULTS: There were no statistically significant differences between BIL and GL in key measures of hepatic (% Ra suppression during the low-dose insulin infusion; 78.7% with BIL, 81.8% with GL) or peripheral (M-value and M/I during the high-dose insulin infusion, Rd and SI) insulin sensitivity in patients with T1DM or T2DM. CONCLUSIONS: The need to reduce prandial insulin observed with BIL during phase 3 trials cannot be explained by the differential effects of BIL and GL on sensitivity to prandial insulin in either T1DM or T2DM.

Lipid changes during basal insulin peglispro, insulin glargine, or NPH treatment in six IMAGINE trials.

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action resulting from reduced peripheral effects. This report provides an integrated summary of lipid changes at 26 weeks with BIL and comparator insulins (glargine, NPH) from phase III studies in type 1 diabetes (T1D), insulin-naïve patients with type 2 diabetes (T2D), patients with T2D on basal insulin only and patients with T2D on basal-bolus therapy. BIL treatment had little effect on HDL cholesterol and LDL cholesterol in all patients. The effect of both BIL and glargine treatment on triglycerides (TG) depended on whether patients had been previously treated with insulin. When BIL replaced conventional insulin glargine or NPH treatments, increases in TG levels were observed. When BIL or comparator insulins were given for 26 weeks to insulin-naïve patients with T2D, TG levels were unchanged from baseline with BIL but decreased with either glargine or NPH. The decreased peripheral action of BIL may reduce suppression of lipolysis in peripheral adipose tissue resulting in increased free fatty acid delivery to the liver and, hence, increased hepatic TG synthesis and secretion.

Relationship of Glucose Variability With Glycated Hemoglobin and Daily Mean Glucose: A Post Hoc Analysis of Data From 5 Phase 3 Studies.

BACKGROUND: The association of glucose variability (GV) with other glycemic measures is emerging as a topic of interest. The aim of this analysis is to study the correlation between GV and measures of glycemic control, such as glycated hemoglobin (HbA1c) and daily mean glucose (DMG). METHODS: Data from 5 phase 3 trials were pooled into 3 analysis groups: type 2 diabetes (T2D) treated with basal insulin only, T2D treated with basal-bolus therapy, and type 1 diabetes (T1D). A generalized boosted model was used post hoc to assess the relationship of the following variables with glycemic control parameters (HbA1c and DMG): within-day GV, between-day GV (calculated using self-monitored blood glucose and fasting blood glucose [FBG]), hypoglycemia rate, and certain baseline characteristics. RESULTS: Within-day GV (calculated using standard deviation [SD]) was found to have a significant influence on endpoints HbA1c and DMG in all 3 patient groups. Between-day GV from FBG (calculated using SD), within-day GV (calculated using coefficient of variation), and hypoglycemia rate were found to significantly influence the endpoint HbA1c in the T2D basal-only group. CONCLUSIONS: Lower within-day GV was significantly associated with improvement in DMG and HbA1c. This finding suggests that GV could be a marker in the early phases of new antihyperglycemic therapy development for predicting clinical outcomes in terms of HbA1c and DMG.

Dose Unit Establishment for a New Basal Insulin Using Joint Modeling of Insulin Dose and Glycemic Response.

BACKGROUND: For new insulin analogs with properties that vary from human insulin, defining activity in units of human insulin based on glycemic lowering efficacy may be challenging. Here we present a new method that can be used to quantify a unit dose of an experimental insulin when the traditional euglycemic clamp method is not adequate. METHODS: Joint modeling of insulin dose and the glycemic outcome variable hemoglobin A1c (HbA1c), where both were response variables, was used to evaluate insulin unit potency for basal insulin peglispro (BIL). The data were from the Phase 3 program for BIL, which included greater than 5500 patients with type 1 or type 2 diabetes who were treated for 26 or 52 weeks with BIL or a comparator insulin. Both basal-bolus and basal insulin only studies were included, and some type 2 diabetes patients were insulin-naïve. RESULTS: The analysis showed that 1 unit of BIL, composed of 9 nmol of active ingredient, had similar or slightly greater potency compared to 1 unit insulin glargine or NPH insulin for all populations. CONCLUSIONS: Despite some limitations, the joint modeling of HbA1c and insulin dose provides a reasonable approach to estimate the relative potency of a new basal insulin versus an established basal insulin.

Cytokeratin-18 and enhanced liver fibrosis scores in type 1 and type 2 diabetes and effects of two different insulins.

Data on cytokeratin-18 (K-18) and enhanced liver fibrosis (ELF) score in insulin-treated diabetes patients with non-alcoholic fatty liver disease (NAFLD) are limited. This study analyzed phase III data comparing basal insulin peglispro (BIL) and insulin glargine in type 1 (T1D), and type 2 diabetes (T2D) (insulin-naïve and insulin-treated). Alanine aminotransferase (ALT), K-18, ELF scores and liver fat content (LFC), measured by MRI, were obtained longitudinally. Baseline K-18 (U/L) was higher in T2D (range: 207‒247) than T1D (range: 148‒183), correlated with ALT in all populations (r (range) 0.264‒0.637, p<0.05), but with LFC only in T2D (r (range) 0.474‒0.586, p<0.05). K-18 increased significantly from baseline in BIL-treated, but not glargine-treated patients. Change from baseline (CFB) K-18 was significantly correlated with CFB in ALT in BIL-treated T2D populations. Baseline ELF scores were higher in T2D (range: 9.12‒9.20) than T1D (range: 8.24‒8.36), correlated with ALT in T1D only (0.209, p<0.05), and not correlated with LFC in any population. ELF scores increased significantly from baseline in BIL-treated but not glargine-treated patients. There were no correlations between CFB in LFC and ELF score at week 52 in any treatment group/population. In all BIL-treated populations, CFB in ALT and CFB in ELF score at week 52 were positively correlated. These data characterize associations of K-18 and ELF score with ALT and LFC in insulin-treated patients with T1D and T2D. Hepatopreferential insulins may be associated with increased K-18 and ELF scores but mechanisms and clinical significance are unknown. ClinicalTrials.gov identifiers are NCT01481779, NCT01435616, NCT01454284 and NCT01582451.

A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia.

OBJECTIVE: Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucose- and lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone. RESEARCH DESIGN AND METHODS: We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n = 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n = 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals. RESULTS: Triglyceride levels were reduced by 51.9 +/- 7.8 mg/dl with pioglitazone, but were increased by 13.1 +/- 7.8 mg/dl with rosiglitazone (P < 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 +/- 0.5 vs. 2.4 +/- 0.5 mg/dl; P < 0.001) and the increase in LDL cholesterol was less (12.3 +/- 1.6 vs. 21.3 +/- 1.6 mg/dl; P < 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P < 0.001). LDL particle size increased more with pioglitazone (P = 0.005). CONCLUSIONS: Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size.

Factors Associated With Cardiovascular Events in Patients With Type 2 Diabetes and Acute Myocardial Infarction.

CONTEXT: Decreasing risk of cardiovascular (CV) disease remains a challenge to survival in type 2 diabetes. OBJECTIVE: The objective was to assess the association between demographic, glycemic, and other clinical factors and CV risk in the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus trial. DESIGN, SETTINGS, PARTICIPANTS, AND INTERVENTION: We used discrete-time survival tree analysis to examine data collected for up to 4.6 years in 1115 patients with type 2 diabetes mellitus experiencing acute myocardial infarction (MI) less than or equal to 18 days before enrollment. MAIN OUTCOME MEASURES: The primary objective was to identify demographic, glycemic, and CV risk factors best separating survival curves over time for a composite end point: CV death, nonfatal MI, nonfatal stroke, hospitalization for acute coronary syndromes, or coronary revascularization planned after randomization. RESULTS: Average change across visits in mean 2-hour blood glucose level after meals was associated with the greatest difference in event-free survival probability for the primary end point: mean time to 75% event-free survival for an average change across visits less than or equal to -0.14 mmol/L, 73.48 weeks; for visits with average change more -0.14 mmol/L, 29.10 weeks. An average change across visits in the hemoglobin A1c level less than or equal to -0.92% (-10.06 mmol/mol) and the absence of a history of stroke or acute MI increased CV event-free survival time further. Fasting blood glucose and randomized insulin treatment strategy were weak predicting factors of event-free survival. CONCLUSIONS: Postprandial glycemia should be considered a potential target in trials to reduce CV morbidity and mortality in type 2 diabetes mellitus.

Control of cardiovascular risk factors in patients with diabetes and hypertension at urban academic medical centers.

OBJECTIVE: There are national mandates to reduce blood pressure (BP) to <130/85 mmHg, LDL cholesterol to <100 mg/dl, and HbA(1c) to <7% and to institute aspirin therapy in patients with diabetes. The objective of this study was to determine the proportion of patients in urban institutions with diabetes and hypertension who meet these treatment goals. RESEARCH DESIGN AND METHODS: Using American Diabetes Association (ADA) guidelines, we evaluated the control of cardiovascular disease (CVD) risk factors in 1,372 patients receiving medical care at two major urban medical centers in Brooklyn and Detroit. Information was extracted from charts of outpatient clinics. RESULTS: Of 1,372 active clinic patients with diabetes and hypertension, 1,247 (90.9%) had type 2 diabetes, and 26.7% met the target blood pressure of 130/85 mmHg. A total of 35.5% met the goal LDL cholesterol level of <100 mg/dl, 26.7% had an HbA(1c) <7%, and 45.6% were on antiplatelet therapy. Only 3.2% of patients met the combined ADA goal for BP, LDL cholesterol, and HbA(1c). CONCLUSIONS: Optimal control of CVD risk factors in adults with diabetes was achieved only in a minority of patients. Results reflect the inherent difficulties in achieving these complex guidelines in our present health care systems.

Glycemic control after 6 days of insulin pump reservoir use in type 1 diabetes: results of double-blind and open-label cross-over trials of insulin lispro and insulin aspart.

BACKGROUND: The objective of the current study was to assess mean self-monitored blood glucose (SMBG), on day 6 of 6 days of continuous reservoir wear (6D), with insulin lispro (Lis) or insulin aspart (Asp). METHODS: Two 24-week, randomized trials were conducted in subjects with type 1 diabetes treated by continuous subcutaneous insulin infusion (CSII) for ≥6 months, with a mean total daily insulin dose capable of supporting 6 days of in-reservoir use. Study 1 had an open-label, six-sequence, three-treatment, three-period, cross-over design. Study 2 had a double-blind, two-sequence, two-treatment, two-period, cross-over design. The primary efficacy measure was the mean of Day 6, seven-point SMBG profiles for insulin lispro 6D (Lis6D) and insulin aspart 6D (Asp6D) treatment periods. Safety measures were also assessed. RESULTS: Lis did not achieve noninferiority (SMBG; margin = 0.6 mmol/L [10.8 mg/dL]) to Asp on Day 6 of reservoir wear in either Study (least-squares mean difference: Study 1 = 0.48 mmol/L [8.64 mg/dL]; 95% confidence interval [CI] [0.20, 0.76], Study 2 = 0.36 mmol/L [6.49 mg/dL]; 95% CI [0.06, 0.66]). Noninferiority was demonstrated for overall daily mean of SMBG values over days 1 to 6 of reservoir use during each treatment period. In the Lis treatment period, subjects reported a lower documented and total hypoglycemia rate per 30 days and a higher rate of non-explained hyperglycemia than in the Asp treatment period. CONCLUSION: While the mean blood glucose on Day 6 of Lis6D did not meet non-inferiority, the overall daily mean blood glucose was not different, with a decreased rate of hypoglycemia with Lis.

Prevalence and risk factors for vaginal Candida colonization in women with type 1 and type 2 diabetes.

BACKGROUND: Diabetes mellitus increases the rate of vaginal colonization and infection with Candida species METHODS: We surveyed women with diabetes receiving care at either an urban or suburban diabetes clinic to examine the relationship between vaginal Candida colonization, diabetes type and duration, and HbA1c level. 101 participants completed the self-administered questionnaire and self-collected a vaginal swab for Candida culture. Candida colonization was similar by age and race. RESULTS: Type 1 diabetics were three times as likely as type 2 diabetics to be colonized with any Candida species (OR = 3.4; 95% CI: 1.03, 11.41; p = 0.04); even after adjusting for abnormal HbA1c, which had an independent effect (OR = 1.4; 95% CI: 1.04, 1.76; p = 0.02). Recent antibiotic use (OR = 4.5; 95% CI: 1.18, 16.79; p = 0.03), lifetime history of chlamydia (OR = 5.8; 95% CI: 1.09, 30.54; p = 0.04), and performing oral sex during the past 2 weeks (OR = 4.9; 95% CI:0.84, 28.27; p = 0.08) were also associated with Candida carriage after adjusting for diabetic type and abnormal HbA1c. C. albicans was isolated from the majority of colonized type 1 participants (56%), while C. glabrata was the most common isolate among colonized type 2 participants (54%). CONCLUSIONS: Improving glucose control and possibly modifying sexual behavior may reduce risk of Candida colonization, and potentially symptomatic infection, among women with diabetes.

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.

A clinical utility index for selecting an optimal insulin dosing algorithm for LY2605541 in patients with type 2 diabetes pretreated with basal insulin.

BACKGROUND: Because insulin dosing requires optimization of glycemic control, it is important to use a single metric of benefit and risk to determine best insulin dosing practices. We retrospectively applied a multiplicative clinical utility index (CUI) to a study of LY2605541 (Eli Lilly and Company, Indianapolis, IN), a novel, long-acting basal insulin. MATERIALS AND METHODS: A CUI was developed to transform the multidimensional problem of assessing benefit/risk of multiple dosing algorithms into a single decision-making metric to evaluate two LY2605541 dosing algorithms relative to the insulin glargine (GL) dosing algorithm. The CUI was applied to data in a 12-week, open-label, Phase 2 trial in patients with type 2 diabetes mellitus who were randomized to one of two dosing algorithms for LY2605541 (LY1 or LY2) or GL (algorithm similar to LY1). The CUI was created (via expert input) by weighing the relative benefit/risk of four components (glycosylated hemoglobin [HbA1c], percentage of patients with HbA1c ≤ 7%, hypoglycemia rate, and time to steady-state dose); individual utility values were multiplied to compute CUI values for LY1 and LY2 relative to GL, and bootstrap samples were used to determine variability. RESULTS: The mean CUI was 0.82 for LY1 and 1.35 for LY2. Based on 3,000 bootstrap samples, there was a 48% probability of LY2 performing better than LY1 and a 28% probability of LY1 performing better than LY2. CONCLUSIONS: CUI methodology, and in particular this CUI, is a useful tool for comparing dosing algorithms. Based on this CUI, LY2 is likely to be a better dosing algorithm than LY1.

Novel PEGylated basal insulin LY2605541 has a preferential hepatic effect on glucose metabolism.

The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg(-1) ⋅ h(-1) [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg(-1) ⋅ h(-1)]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg(-1) ⋅ min(-1) within 5 h in control, LY0.25, LY0.375, and LY0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg(-1) ⋅ min(-1) in all groups, was higher in control (1.17 ± 0.38) versus LY0.25 (0.39 ± 0.33), LY0.375 (-0.01 ± 0.13), and LY0.5 (-0.09 ± 0.07). Likewise, the change from baseline in glucose Rd-to-Ra ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY0.25, LY0.375, and LY0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.

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.

Rate of hypoglycemia in insulin-treated patients with type 2 diabetes can be predicted from glycemic variability data.

BACKGROUND: We set out to study the relationship between different measures of glycemic variability and the rate of hypoglycemia in patients with type 2 diabetes. SUBJECTS AND METHODS: Data were pooled from three 24-week insulin trials including patients on twice-daily (BID) insulin lispro mix 75/25 (75% insulin lispro protamine suspension, 25% insulin lispro) (n=805), daily (QD) insulin glargine (n=1,019), insulin lispro protamine suspension (n=353) (QD or BID), and insulin detemir (n=166) (QD or BID), all with continuation of prestudy oral antihyperglycemic medications. Glycemic variability measures were derived from seven-point self-monitored blood glucose profiles. RESULTS: At baseline, mean (±SD) age was 56.9±9.7 years, duration of type 2 diabetes was 9.5±6.1 years, hemoglobin A1c (HbA1c) was 8.9±1.1%, and 51.9% were male. Intra-day glucose coefficient of variation (CV), fasting blood glucose, intra-day minimum glucose and inter-day glucose CV at 24 weeks, and intra-day glucose CV at baseline were significantly correlated with the rate of hypoglycemia events between Weeks 12 to 24 (P<0.05 for all measures). CONCLUSIONS: Intra-day and inter-day glycemic variability is significantly associated with the risk of hypoglycemia in insulin-treated patients with type 2 diabetes, even after adjusting for mean glucose and HbA1c. The intra-day glycemic variability before starting insulin is significantly associated with the risk of hypoglycemia during insulin treatment, which points at treatment- and patient-related factors mediating this relationship.

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.