Glucose Infusion Rate Profiles Research Articles

Insulin glargine 300 U/ml in type 2 diabetes mellitus patients: results of the EDITION program (review)

Unmet medical needs in basal insulin therapy include late initiation of therapy, hypoglycemia, and low patient compliance. Introduction of new basal insulin may cater to these unmet medical needs.
 New insulin glargine 300 U/mL (Gla-300) (Toujeo) is a long-acting basal insulin with a more even and prolonged PK/PD profile compared to those of insulin glargine 100 (Lantus). The glucose infusion rate profiles and insulin concentration of Gla-300 were more constant and more evenly distributed over 24 h compared to those of glargine 100 U/mL. Stable blood glucose control (≤ 5.5 mmol/L) was maintained approximately 5 h longer with glargine 300 U/mL compared to glargine 100 U/mL. The difference in PK/PD profiles of glargine 300 U/mL and glargine 100 U/mL may be a key to explanation of the Toujeo® clinical features demonstrated in the EDITION program.
 This review discusses the EDITION clinical program results in type 2 diabetes mellitus (T2MD) patients, except EDITION JP2: on previous basal-bolus therapy (EDITION 1, n=807), previous basal insulin in combination with oral anti-diabetic drug (EDITION 2, n=811), and insulin naive patients (oral anti-diabetic drug excl. SU) (EDITION 3, n=878). The EDITION program was aimed to assess the efficacy and safety of Gla-300 compared to those of glargine 100 U/mL. EDITION programs were multicenter, 1:1 randomized, open-label, parallel group, phase III, and non-inferiority studies, with similar designs and endpoints. The primary endpoint was the non-inferiority of Gla-300 vs glargine 100 U/mL, which was estimated as a HbA1c reduction at 6 months. The main secondary endpoint was the percentage of participants with one or more nocturnal confirmed (≤3.9 mmol/L) or severe hypoglycemic events from week 9 to month 6 of treatment. Patients were randomized to glargine 300 U/mL or glargine 100 U/mL once a day, with dose titration seeking fasting plasma glucose of 4.4—5.6 mmol/L.
 Non-inferiority of glargine 300 U/mL in the HbA1C reduction vs glargine 100 U/mL was confirmed in EDITION 1, EDITION 2, and EDITION 3 studies. According to the results of a pool analysis of these three trials, annualized rates of confirmed (≤3.9 mmol/L) or severe hypoglycemia were lower with glargine 300 U/mL than with glargine 100 U/mL during the night (31% difference in the rate ratio over 6 months, p=0.0002) and at any time (24 h, 14% difference, p=0.0116). Severe hypoglycemia at any time was rare (glargine 300 U/mL: 2.3%; glargine 100 U/mL: 2.6%). Weight gain was low (<1 kg) in both groups, with the gain being less with glargine 300 U/ml [LS mean difference —0.28 kg (95% CI –0.55 to –0.01); p=0.039]. Both treatments were well tolerated, having similar rates of adverse events.
 In conclusion, glargine 300 U/mL was characterized by the non-inferior efficacy compared to glargine 100 U/mL, a better safety profile (reduced hypoglycemia), and lower weight gain. These advantages may allow for more active insulin dose titration in real clinical practice, contribute to better-sustained glycemic control and patient compliance, and, consequently, improve the prognosis and clinical outcome.

A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects.

Technosphere insulin (TI), an inhaled insulin with a fast onset of action, provides a novel option for the control of prandial glucose. A euglycemic glucose clamp study was performed to compare the effects of TI and regular human insulin (RHI) on the induced glucose infusion rate (GIR) in healthy volunteers. Generation of a dose–response relationship between insulin dose and effect (expressed as AUC of GIR) was not possible from the clinical data directly. The GIR recording time was too short to capture the full effect and higher doses were not tested. Thus, a pharmacokinetic‐GIR model was developed to simulate GIR for a sufficient time window of 20 h and for higher doses. A dose–response model was then generated from the simulated GIR profiles. The resulting model provides an ED50 for TI that is 5‐fold higher than for RHI, a ratio that can be used as conversion factor for equivalent doses of RHI and TI.

The Distinct Prandial and Basal Pharmacodynamics of IDegAsp Observed in Younger Adults Are Preserved in Elderly Subjects with Type 1 Diabetes.

BackgroundManagement of diabetes in elderly patients is complicated by the elevated risk of insulin-induced hypoglycaemia. This is the first study to report the pharmacodynamic and pharmacokinetic characteristics of IDegAsp (insulin degludec [IDeg]/insulin aspart [IAsp]), a soluble co-formulation of a long-acting basal insulin analogue (IDeg) and a rapid-acting insulin analogue (IAsp) in a single injection, in elderly and younger adult subjects with type 1 diabetes using a glucose clamp.MethodsIn this randomised, single-centre, double-blind, single-dose (SD), two-period, crossover trial, 15 elderly subjects (aged ≥65 years) and 13 younger adults (aged 18–35 years) with type 1 diabetes were randomly assigned to two SD administrations of 0.5 U/kg IDegAsp or biphasic insulin aspart 30 (control) followed by a 26-h euglycaemic glucose clamp and 120-h pharmacokinetic blood sampling. The glucose infusion rate (GIR) profiles were extrapolated to simulated steady-state (SS) conditions using pharmacodynamic models.ResultsIDegAsp GIR profiles showed a distinct peak and rapid onset of action from IAsp followed by a separate and flat basal action from IDeg. Mean 24-h area under the GIR curve was similar in elderly subjects vs. younger adults (mean ratio 1.01 [95 % confidence interval 0.69–1.47]). Simulated SS pharmacodynamic profiles with once-daily IDegAsp showed a parallel upshift in GIR profiles vs. SD profiles. The shape of the IDegAsp pharmacodynamic profile was retained with twice-daily dosing under simulated SS conditions. IDegAsp was well tolerated.ConclusionsThe distinct prandial and basal pharmacodynamics of IDegAsp observed in younger adults were preserved in elderly subjects with type 1 diabetes. The glucose-lowering effect of IDegAsp was similar in elderly subjects and younger adults with type 1 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s40266-015-0272-y) contains supplementary material, which is available to authorized users.

Comparison of the pharmacokinetic and pharmacodynamic profiles of insulin degludec and insulin glargine

Objectives: A medical need remains for a once-daily insulin with 24-h basal coverage in all patients. We characterize the steady-state (SS) pharmacokinetic/pharmacodynamic properties of insulin degludec (IDeg) versus insulin glargine (IGlar).Research design and methods: In this controlled, single-center study, 66 type 1 diabetes patients were randomized to two 8-day periods of once-daily IDeg or IGlar at 0.4, 0.6 or 0.8 U/kg. At SS, subjects underwent a 42-h euglycemic glucose clamp (5.5 mmol/l; 100 mg/dl). Glucose infusion rate (GIR), distribution of GIR and half-life were assessed.Results: Mean 24-h GIR profiles were flatter and more stable for all doses of IDeg versus IGlar. The evenly distributed glucose-lowering effect of IDeg was confirmed by the AUCGIR across one dosing interval, as each of the four 6-h intervals across one dosing interval contributed ∼ 25% of the AUCGIR,τ,SS. IGlar was most effective during the first 12 – 18 h after dosing. At SS, the half-life was 25.4 (IDeg) versus 12.1 h (IGlar). No safety concerns were identified for IDeg or IGlar.Conclusion: IDeg has a longer half-life (> 25 h) than IGlar. Exposure and glucose-lowering effects are more stable and evenly distributed across one dosing interval for IDeg versus IGlar (Clinical trials.gov identifier: NCT01114542).

Single‐dose pharmacokinetics and glucodynamics of the novel, long‐acting basal insulin LY2605541 in healthy subjects

LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01-2.22 U/kg) and insulin glargine (0.5-0.8 U/kg) followed by euglycemic clamp for up to 24-36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time-to-maximum plasma concentration (medians) and geometric means for half-life (t½ ) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4-45.5 hours, and 1.8-2.8 L/h for SC LY2605541, versus 10.0-12.0 hours, 12.2-14.9 hours, and 51.4-65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541's geometric mean t½ was 2.3 hours. LY2605541 intra-subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild-moderate in severity. These results established a well-tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra-subject variability.

The Pharmacokinetic and Pharmacodynamic Properties of Biphasic Insulin Aspart 70 (BIAsp 70) are Significantly Different from those of Biphasic Insulin Aspart 30 (BIAsp 30)

To evaluate the pharmacokinetic and pharmacodynamic properties of two different formulations of premixed analogue (mixed biphasic insulin aspart [BIAsp]), BIAsp 30 (30 % soluble insulin aspart [IAsp] and 70 % protaminated IAsp) and BIAsp 70 (70 % soluble IAsp and 30 % protaminated IAsp), in patients with type 1 diabetes using a 12-hour euglycaemic clamp technique. In this randomised, double-blind, two-period crossover trial, 27 patients with type 1 diabetes received 7 days of treatment with BIAsp 30 three times daily (TID) and 7 days of treatment with BIAsp 70 TID, with a 2 - 6 week washout period between treatment periods. At the start (day 1) and end (day 8) of each treatment period, 12-hour serum IAsp profiles and glucose infusion rate (GIR) profiles were determined during an overnight euglycaemic clamp following subcutaneous (sc) administration of a single 0.3 U/kg dose of trial insulin. All pharmacokinetic and pharmacodynamic endpoints were derived from individual serum IAsp and GIR profiles. The larger fraction of soluble IAsp in BIAsp 70 compared with BIAsp 30 resulted in greater metabolic effect during the initial post-dosing phase (0 - 6 hours) and decreased activity during the late phase (6 - 12 hours). On day 8, AUC (GIR 0 - 6 hours) was 16 % greater for BIAsp 70 than for BIAsp 30 (p = 0.016) and AUC (GIR 6 - 12 hours) was 90 % (p < 0.001) greater for BIAsp 30 relative to BIAsp 70, reflecting the increased proportion of intermediate-acting (protamine co-crystallised) IAsp in BIAsp 30. Overall metabolic effect (AUC (GIR 0 - 12 hours)) was similar for both insulin formulations on day 8 (Ratio, BIAsp 30:BIAsp 70 = 1.04, p = 0.538). Likewise, the larger fraction of soluble IAsp in BIAsp 70 compared with BIAsp 30 resulted in greater exposure to IAsp during the initial post-dosing phase (0 - 6 hours) and a smaller exposure to IAsp during the late phase (6 - 12 hours). On day 8, AUC (IAsp 0 - 6 hours) was 59 % (p < 0.001) greater for BIAsp 70 than for BIAsp 30, and AUC (IAsp 6 - 12 hours) was 61 % (p < 0.001) greater for BIAsp 30 than for BIAsp 70, reflecting the increased proportion of intermediate-acting (protamine co-crystallised) IAsp in BIAsp 30. However, the overall IAsp exposure (AUC 0 - 12 hours) on day 8 was significantly greater for BIAsp 70 than for BIAsp 30 (Ratio, BIAsp 30:BIAsp 70 = 0.73, p < 0.001). The GIR profiles on day 8 were similar to those on day 1. Serum IAsp profiles on day 8 showed a slight increase compared with day 1. The different proportions of soluble and protaminated IAsp result in differences in the pharmacokinetic and pharmacodynamic properties of BIAsp 30 and BIAsp 70. The pharmacokinetic and pharmacodynamic differences observed may allow for flexibility and individualised treatment regimens in patients with diabetes, while maintaining a limited number of daily injections.