New Clamp-PID Algorithm for Automated Glucose Clamps Improves Clamp Quality.

BACKGROUND: In automated glucose clamp experiments, blood glucose (BG) concentrations are kept close to a predefined target level using variable glucose infusion rates (GIRs) determined by implemented algorithms. Clamp quality (ie, the ability to keep BG close to target) highly depends on the quality of these algorithms. We developed a new Clamp algorithm based on the proportional-integral-derivative (PID) approach and compared clamp quality between this and the established Biostator (BS) algorithm. METHODS: In numerical simulations, the PID-based algorithm was optimized in silico. The optimized Clamp-PID algorithm was tested in in vitro experiments and finally validated in vivo in a small (n = 5) clinical study. RESULTS: In silico, in vitro, and in vivo experiments showed better clamp quality for the new Clamp-PID algorithm compared with the BS algorithm: precision and absolute control deviation (ACD) decreased from 3.7% to 1.1% and from 2.9 mg/dL to 0.6 mg/dL, respectively, in the numerical simulation. The in vitro validation demonstrated reductions in precision (from 3.3% ± 0.1% (mean ± SD) to 1.4% ± 0.4%) and in ACD (from 2.3 mg/dL ± 0.4 mg/dL to 0.8 mg/dL ± 0.2 mg/dL), respectively. In the clinical study, precision and ACD improved from 6.5% ± 1.3% to 4.0% ± 1.1% and from 3.6 mg/dL ± 0.9 mg/dL to 2.2 mg/dl ± 0.6 mg/dl, respectively. The quality parameter utility did not change. CONCLUSIONS: The new Clamp-PID algorithm improves the clamp quality parameters precision and ACD versus the BS algorithm.

A single-dose euglycaemic clamp study in two cohorts to compare the exposure of SAR341402 (insulin aspart) Mix 70/30 with US- and European-approved versions of insulin aspart Mix 70/30 and SAR341402 rapid-acting solution in subjects with type 1 diabetes.

AIM: To compare the pharmacokinetic exposure of SAR341402 Mix 70/30 (SARAsp -Mix) with US- and European (EU)-approved versions of insulin aspart Mix 70/30 (NovoLog Mix 70/30 [NN-Mix-US]/NovoMix 30 [NN-Mix-EU]) and SAR341402 insulin aspart solution (SAR-Asp) in subjects with type 1 diabetes. MATERIALS AND METHODS: This was a randomized, double-blind, crossover trial in two cohorts. Fifty-two subjects received a single subcutaneous 0.3 U/kg dose of each treatment and underwent a euglycaemic clamp procedure lasting for a maximum of 24 hours after dosing. In cohort 1, subjects (N = 36) were exposed once each to SARAsp -Mix, NN-Mix-US and NN-Mix-EU. In cohort 2, subjects (N = 16) were exposed once each to SARAsp -Mix and SAR-Asp. RESULTS: Of the 52 subjects randomized, 48 completed all treatment periods. In cohort 1, the extent of exposure (total and maximum concentration) was similar among the three treatments, with the 90% confidence intervals for pairwise treatment ratios meeting the predefined acceptance range (0.80 to 1.25). In cohort 2, statistically significant differences (P < .001) in early (0-4 hours) and intermediate (4-12 hours) exposure to SARAsp -Mix compared with SAR-Asp were observed, all exceeding a 20% difference. Pharmacodynamic results were in support of the pharmacokinetic findings for both cohorts. All treatments were well tolerated and there were no relevant differences in safety variables among treatments. CONCLUSIONS: SARAsp -Mix showed similar pharmacokinetic exposure to commercially available insulin aspart Mix 70/30 formulations, and a distinct exposure profile compared with SAR-Asp.

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

BACKGROUND AND OBJECTIVE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. RESULTS: Insulin lispro appeared in the serum 5 min faster (p < 0.0001) and exposure was 6.4-fold greater in the first 15 min (p < 0.0001) with URLi versus Humalog. Exposure beyond 3 h postdose was 26% lower and the duration of exposure was 51 min shorter with URLi versus Humalog. Onset of insulin action was 13 min faster (p < 0.0001) and insulin action was 4.2-fold greater within the first 30 min (p < 0.0001) with URLi versus Humalog. Insulin action beyond 4 h postdose was 20% lower (p = 0.0099) with URLi versus Humalog. Overall insulin lispro exposure and total glucose infused were similar for URLi and Humalog. Both treatments were well tolerated. CONCLUSIONS: This is the first study to investigate URLi in patients with T2DM using a euglycaemic clamp procedure. URLi demonstrated ultra-rapid pharmacokinetics and glucodynamics in patients with T2DM. CLINICALTRIALS. GOV IDENTIFIER: NCT03305822.

Single-Dose Euglycemic Clamp Study Demonstrating Pharmacokinetic and Pharmacodynamic Similarity Between SAR341402 Insulin Aspart and US- and EU-Approved Versions of Insulin Aspart in Subjects with Type 1 Diabetes.

Background: The objective of this study was to demonstrate the pharmacokinetic and pharmacodynamic similarity among SAR341402 insulin aspart biosimilar/follow-on product, United States-sourced insulin aspart (NovoLog®), and European Union-sourced insulin aspart (NovoRapid®). Materials and Methods: This was a single-center, randomized, double-blind, 3-treatment, 3-period, single-dose, crossover euglycemic study (NCT03202875) in 30 adult male subjects with type 1 diabetes (T1D). Subjects received 0.3 U/kg of each treatment under fasted conditions and underwent a 12-h euglycemic clamp technique to assess pharmacokinetic and pharmacodynamic activity for up to 12 h. Primary endpoints were area under the plasma insulin concentration-time curve from time zero to the last quantifiable concentration (INS-AUClast), and extrapolated to infinity (INS-AUCinf), maximum plasma insulin concentration (INS-Cmax), and the area under the body weight-standardized glucose infusion rate (GIR)-time curve from 0 to 12 hours (GIR-AUC0-12h) among the three treatments. GIRmax was the main secondary endpoint. Results: Of the 30 subjects randomized, 29 completed all 3 treatment periods. Pharmacokinetic and pharmacodynamic profiles were similar in all groups. The extent of exposure (INS-Cmax, INS-AUClast, and INS-AUCinf) and glucodynamic activity (GIR-AUC0-12h, GIRmax) was similar among the three treatments. The corresponding 90% confidence intervals for pairwise treatment ratios were completely contained within the limits of 80%-125%. SAR341402 was well tolerated. Conclusions: The present study demonstrated similar pharmacokinetic exposure profiles and glucodynamic potency among SAR341402, NovoLog, and NovoRapid in subjects with T1D, supporting further clinical evaluation of SAR341402 as a biosimilar/follow-on product.

Investigation of Pump Compatibility of Fast-Acting Insulin Aspart in Subjects With Type 1 Diabetes.

BACKGROUND: Ultra-fast-acting insulins, such as fast-acting insulin aspart (faster aspart), have pharmacokinetic properties that may be advantageous for patients using continuous subcutaneous insulin infusion (CSII), provided that they are compatible with and safe to use in CSII. METHODS: Randomized, double-blind, parallel-group, actively controlled trial evaluating compatibility, efficacy, and safety of faster aspart in adults with type 1 diabetes using their own MiniMed Paradigm pump with Quick-Set or Silhouette infusion sets. Following run-in, subjects were randomized (2:1) to faster aspart (n = 25) or insulin aspart (n = 12) for 6 weeks. Primary endpoint was the number of microscopically confirmed episodes of infusion-set occlusions. RESULTS: No microscopically confirmed episodes of infusion-set occlusions were observed in either arm. Seven possible infusion-set occlusions were reported by five subjects (all faster aspart); none were prompted by a plug observed by the subject (prompted by unexplained hyperglycemia [n = 6] or leakage [n = 1]) and none were confirmed. Macroscopic and microscopic evaluation showed no color change or particle/crystal formation in the infusion sets. Premature infusion-set changes were reported in 44% and 16.7% of subjects in the faster aspart and insulin aspart groups, respectively. A nonsignificant trend toward better efficacy was observed with faster aspart (estimated treatment difference [ETD] [95% CI] in HbA1c change: -0.14% [-0.40, 0.11]). No new safety issues were found in either treatment group. CONCLUSIONS: Over 6 weeks of treatment, no microscopically confirmed infusion-set occlusions were observed for faster aspart or insulin aspart, indicating similar compatibility with CSII use.

Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes.

AIM: To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300 U/mL (IGlar-U300) in type 1 diabetes. MATERIALS AND METHODS: In this double-blind, crossover study, patients were randomly assigned to 0.4 U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12 days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic glucose clamps (days 6, 9 and 12) during each treatment period. RESULTS: Overall, 57 patients completed both treatment periods (342 clamps). The potency of IGlar-U300 was 30% lower than IDeg (estimated ratio 0.70, 95% confidence interval [CI] 0.61; 0.80; P < .0001). The distribution of glucose-lowering effect was stable across 6-hour intervals (24%-26%) for IDeg, while IGlar-U300 had greater effects in the first (35%) and last (28%) intervals compared with 6 to 12 hours (20%) and 12 to 18 hours (17%). Within-day variability (relative fluctuation) was 37% lower with IDeg than with IGlar-U300 (estimated ratio IDeg/IGlar-U300: 0.63, 95% CI 0.54; 0.73; P < .0001). The day-to-day variability in glucose-lowering effect with IDeg was approximately 4 times lower than IGlar-U300 (variance ratio IGlar-U300/IDeg: 3.70, 95% CI 2.42; 5.67; P < .0001). The day-to-day variability in glucose-lowering effect assessed in 2-hour intervals was consistently low with IDeg over 24 hours, but steadily increased with IGlar-U300 to a maximum at 10 to 12 hours and 12 to 14 hours after dosing (variance ratios 12.4 and 11.4, respectively). CONCLUSION: IDeg has lower day-to-day and within-day variability than IGlar-U300 and a more stable glucose-lowering effect, which might facilitate titration and enable tighter glycaemic control with a reduced risk of hypoglycaemia.

Pharmacokinetic Properties of Fast-Acting Insulin Aspart Administered in Different Subcutaneous Injection Regions.

BACKGROUND: Fast-acting insulin aspart (faster aspart) is insulin aspart set in a new formulation with faster initial absorption after subcutaneous administration. This study investigated the pharmacokinetic properties, including the absolute bioavailability, of faster aspart when administered subcutaneously in the abdomen, upper arm or thigh. METHODS: In a randomised, open-label, crossover trial, 21 healthy male subjects received a single injection of faster aspart at five dosing visits: 0.2 U/kg subcutaneously in the abdomen, upper arm and thigh, intramuscularly in the thigh and 0.02 U/kg intravenously. Blood sampling for pharmacokinetics was performed pre-dose and frequently thereafter until 12 h post-dose (8 h after intravenous administration). RESULTS: Onset of appearance (~3 min), time to 50% of maximum concentration (t Early 50% Cmax; ~20 min) and time to maximum concentration (t max; ~55 min) were all similar between injection regions. Early exposure within the first 2 h after injection (AUCIAsp,0-1h and AUCIAsp,0-2h) as well as maximum concentration (C max) were comparable for the abdomen and upper arm, but were ~25% lower for the thigh as seen previously for other mealtime insulin products. Total exposure (AUCIAsp,0-t) was similar for the abdomen, upper arm and thigh, and absolute bioavailability was ~80% after subcutaneous administration of faster aspart in all three injection regions. CONCLUSION: The current study supports the ultra-fast pharmacokinetic characteristics of faster aspart across different injection regions, with administration in the abdomen and upper arm resulting in greater early exposure than in the thigh. ClinicalTrials.gov identifier: NCT02089451.

Similar pharmacokinetics and pharmacodynamics of rapid-acting insulin lispro products SAR342434 and US- and EU-approved Humalog in subjects with type 1 diabetes.

AIM: To compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 rapid-acting insulin lispro products: SAR342434 solution, United States (US)-approved Humalog and European Union (EU)-approved Humalog. METHODS: In a single-centre, randomized, double-blind, 3-treatment, 3-period, 6-sequence, crossover, euglycaemic clamp study (NCT02273258), adult male subjects with type 1 diabetes were randomized to receive 0.3 U/kg of SAR342434 solution, US-approved and EU-approved Humalog under fasted conditions. PK and PD (glucose infusion rate [GIR]) were assessed up to 12 hours. RESULTS: Of the 30 subjects randomized, 28 completed all 3 treatment periods. Mean concentration and GIR vs time profiles were similar for all 3 products. Exposure (INS-Cmax , INS-AUClast and INS-AUC) and activity (GIRmax and GIR-AUC0-12h ) of SAR342434, US-approved and EU-approved Humalog were similar in all comparisons (point estimates of treatment ratios, 0.95-1.03 for PK parameters and 1.00-1.07 for PD parameters), with 90% confidence intervals for the ratios of geometric least squares means within the pre-specified bioequivalence limit (0.80-1.25) and no significant differences in time-related parameters. Within-subject variability of exposure and activity was low across the 3 clamps, indicating high day-to-day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for all 3 products. No safety concerns were noted in vital signs or in laboratory and electrocardiogram data. CONCLUSIONS: The results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US- and EU-approved Humalog, and between both US- and EU-approved Humalog, supporting the use of SAR342434 solution for injection as a follow-on product.

Pharmacological properties of faster-acting insulin aspart vs insulin aspart in patients with type 1 diabetes receiving continuous subcutaneous insulin infusion: A randomized, double-blind, crossover trial.

AIM: To evaluate the pharmacological characteristics of faster-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp) during continuous subcutaneous insulin infusion (CSII). METHODS: In this randomized, double-blind, crossover trial, 48 men and women aged 18 to 64 years with type 1 diabetes mellitus (T1DM) received faster aspart and IAsp as a 0.15 U/kg bolus dose via CSII, on top of a basal rate (0.02 U/kg/h), in a glucose clamp setting (target 5.5 mmol/L). RESULTS: After a CSII bolus dose, the pharmacokinetic/pharmacodynamic profiles for faster aspart were left-shifted compared with those for IAsp. For faster aspart vs IAsp, the early glucose-lowering effect (area under the curve for glucose infusion rate [GIR]0-30min ) was approximately 2-fold higher (least squares means 24.9 vs 11.4 mg/kg; estimated ratio faster aspart/IAsp 2.18, 95% confidence interval [CI] [1.33; 5.04]; P = .002), onset of glucose-lowering effect (time to early 50% of maximum GIR) occurred 11.1 minutes earlier (41.1 vs 52.3 minutes; 95% CI faster aspart - IAsp [-15.4; -6.9]; P<.001), and offset of glucose-lowering effect (time to late 50% of maximum GIR) occurred 24.0 minutes earlier (214.7 vs 238.7 minutes; 95% CI [-38.9; -9.1]; P=.002). Likewise, significantly greater early exposure and significantly earlier onset and offset of exposure were observed for faster aspart vs IAsp. Faster aspart and IAsp were both well tolerated. CONCLUSIONS: In patients with T1DM using CSII, faster aspart better mimics the endogenous prandial insulin secretion and action than does IAsp. Faster aspart therefore has the potential to provide clinical benefits over current rapid-acting insulins in the insulin pump setting.

Pharmacokinetic and Pharmacodynamic Properties of Faster-Acting Insulin Aspart versus Insulin Aspart Across a Clinically Relevant Dose Range in Subjects with Type 1 Diabetes Mellitus.

BACKGROUND: Absorption of current rapid-acting insulins is too slow for patients with diabetes mellitus to achieve optimal postprandial glucose control. Faster-acting insulin aspart (faster aspart) is insulin aspart in a new formulation with faster early absorption. We compared the pharmacokinetic/pharmacodynamic properties of faster aspart and insulin aspart across a clinically relevant dose range. METHODS: In this randomised, double-blind, crossover trial, 46 subjects with type 1 diabetes mellitus received single subcutaneous doses of faster aspart and insulin aspart at 0.1, 0.2 (repeated three times to estimate within-subject variability) and 0.4 U/kg in a euglycaemic clamp setting (target 5.5 mmol/L). RESULTS: Consistently for the three doses, faster aspart demonstrated faster onset and greater early absorption and glucose-lowering effect versus insulin aspart. Across all three doses, onset of appearance occurred approximately twice as fast (approximately 5 min earlier) and early insulin exposure (AUCIAsp,0-30min) was approximately 1.5- to 2-fold greater for faster aspart versus insulin aspart. Likewise, onset of action occurred approximately 5 min faster and early glucose-lowering effect (AUCGIR,0-30min) was approximately 1.5- to 2-fold larger for faster aspart versus insulin aspart. Relative bioavailability was approximately 100% and total glucose-lowering effect was similar for faster aspart versus insulin aspart. Dose-concentration and dose-response relationships were comparable between faster aspart and insulin aspart. Within-subject variability in glucose-lowering effect was low for faster aspart (coefficient of variation approximately 20%) and not significantly different from insulin aspart. CONCLUSION: The faster onset and greater early insulin exposure and glucose-lowering effect with faster aspart versus insulin aspart are preserved across a broad range of doses and consistently observed from day to day. CLINICALTRIALS. GOV IDENTIFIER: NCT02033239.

Euglycaemic glucose clamp: what it can and cannot do, and how to do it.

The hyperinsulinaemic-euglycaemic glucose clamp has always been regarded as the "gold standard" for the assessment of pharmacodynamic (PD) properties of insulin preparations; however, there has been controversy over a variety of methodogical details, such as study population, dosing time and the initial stabilization of blood glucose (BG) concentrations at the clamp target level, among clamp groups. As the impact of these details on PD results is unclear, the present review provides an overview of different methodological approaches for both the manual and the automated hyperinsulinaemic-euglycaemic glucose clamp. The advantages and limitations of several methodological details are discussed as well as the relevance of clamp results for the prediction of clinical outcomes. Overall, the best method strongly depends on the exact objective of the trial. If, for instance, duration of action is the primary objective, studies should be carried out in patients with type 1 diabetes to avoid any interference of endogenous insulin. This is less important for variables such as onset of action or early metabolic activity. The hyperinsulinaemic-euglycaemic glucose clamp has a high sensitivity to detect even minor differences between different insulin preparations. The practical relevance of potential differences, however, needs to be investigated in clinical studies. A major prerequisite for obtaining reliable glucose clamp results is the attainment of high clamp quality (i.e. keeping BG concentrations close to the clamp target throughout the experiments). Unfortunately, measures of clamp quality are often under-reported, as is the variability in PD profiles, although these might explain some unconfirmed extreme results obtained in a few clamp studies.

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes.

AIMS/HYPOTHESIS: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower glycaemia by inducing glycosuria, but raise endogenous glucose production (EGP). Metformin lowers glycaemia mainly by suppressing EGP. We compared the effects of the SGLT2 inhibitor empagliflozin in treatment-naive (TN) and metformin pretreated (Met) patients with type 2 diabetes. METHODS: A total of 32 TN and 34 patients on a stable dose of metformin, two subgroups of a study that we previously reported, received a mixed meal with double-tracer glucose administration and indirect calorimetry at baseline, after a single 25 mg dose of empagliflozin, and after 4 weeks of treatment with empagliflozin 25 mg/day. RESULTS: At baseline, compared with the TN group, the Met group had higher fasting glycaemia (9.1 ± 1.7 vs 8.2 ± 1.3 mmol/l), lower fasting and postmeal insulin secretion, lower beta cell glucose sensitivity (37 [18] vs 58 [43] pmol min(-1) m(-2) [mmol/l](-1), median [interquartile range]) and insulin:glucagon ratio, and higher fasting EGP (15.9 [4.3] vs 12.1 [2.7] µmol kgFFM (-1) min(-1)). Change from baseline in fasting EGP after single dose and 4 weeks of treatment with empagliflozin was similar in the Met and TN groups (19.6 [4.2] and 19.0 [2.3] in Met vs 16.2 [3.6] and 15.5 [3.2] µmol kgFFM (-1) min(-1) in TN for acute and chronic dosing, respectively). Beta cell glucose sensitivity increased less in Met than TN patients, whereas substrate utilisation shifted from carbohydrate to fat more in Met than TN patients. CONCLUSIONS/INTERPRETATION: At baseline, Met patients with type 2 diabetes had more advanced disease than TN patients, featuring worse beta cell function and higher EGP. Empagliflozin induced similar glycosuria and metabolic and hormonal responses in Met and TN patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01248364; European Union Clinical Trials Register 2010-018708-99.

Steady state is reached within 2-3 days of once-daily administration of degludec, a basal insulin with an ultralong duration of action.

BACKGROUND: Various factors influence the pharmacokinetic and pharmacodynamic properties of insulin analogs. The aim of the present study was to determine time to steady state of insulin degludec (IDeg), a basal insulin analog with an ultralong duration of action, after once-daily subcutaneous administration in subjects of varying age, diabetes type, and ethnicity. METHODS: Time to steady state was analyzed in 195 subjects across five Phase I randomized single-center double-blind studies: three in subjects with type 1 diabetes (T1DM), including one in elderly subjects, and two in subjects with type 2 diabetes (T2DM), including one with African American and Hispanic/Latino subpopulations. Subjects received once-daily IDeg (100 U/mL, s.c.) at doses of 0.4-0.8 U/kg for 6-12 days. Time to clinical steady state was measured from first dose until the serum IDeg trough concentration exceeded 90% of the final plateau level. The IDeg concentrations were log-transformed and analyzed using a mixed-effects model with time from first dose and dose level (where applicable) as fixed effects, and subject as a random effect. RESULTS: Steady state serum IDeg concentrations were reached after 2-3 days in all subjects. In trials with multiple dose levels, time to steady state was independent of dose level in T1DM (P = 0.51) and T2DM (P = 0.75). CONCLUSIONS: Serum IDeg concentrations reached steady state within 2-3 days of once-daily subcutaneous administration in all subjects with T1DM or T2DM, including elderly and African American and Hispanic/Latino subjects. At steady state, serum IDeg concentrations were unchanged from day to day.

Intradermal insulin infusion achieves faster insulin action than subcutaneous infusion for 3-day wear.

Rapid uptake previously demonstrated by intradermal (ID) drug administration indicates compound delivery within the dermis may have clinical and pharmacological advantages for certain drug therapies. This study is the first clinical trial to evaluate continuous microneedle-based drug infusion, device wearability, and intradermal microneedle insulin kinetics over a multi-day (72 h) wear period. This was a single center, open-label, two-period crossover study in T1DM patients on continuous subcutaneous insulin infusion (CSII). Patients received treatment during interventional visits: one SC and one ID basal/bolus infusion of insulin aspart (NovoRapid® U-100) administered over 3 days in a randomized order. Twenty-eight patients were randomized and exposed to trial product, and 23 completed the study. Bolus insulin infusions were given prior to standardized breakfast and lunch test meals on each of the three treatment days. Blood samples were drawn at predefined time points for measurements of insulin aspart and blood glucose in serum. The primary endpoint insulin Tmax demonstrated that ID bolus infusion was associated with a significantly shorter Tmax with statistically significantly smaller intra-subject variability, compared to SC infusion, and this difference was maintained over three treatment days. Analyses of secondary PK endpoints corresponded with the primary endpoint findings. Postprandial glycemic response was significantly less pronounced after ID bolus: For most endpoints ID vs. SC, differences were statistically significant within the 0-1.5 or 0-2 h time period. Intradermal delivery of insulin is a viable delivery route alternative providing reduced time for insulin absorption with less intra-subject variability and lower glycemic response.

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).

Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel.

The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80-1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0-24 h ) for semaglutide steady-state/semaglutide-free; 1.11 (1.06-1.15). AUC0-24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15-1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (-1.1 ± 0.6%) and weight (-4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel.

Glucose-lowering effect of insulin degludec is independent of subcutaneous injection region.

BACKGROUND AND OBJECTIVES: Patients with diabetes mellitus inject insulin in different regions of the body. This study investigated the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a new-generation once-daily basal insulin with an ultra-long duration of action, after subcutaneous (SC) administration in different injection regions. METHODS: In this study, 20 healthy subjects received single SC doses of IDeg (0.4 U/kg; separated by 13-21 days) in the thigh, abdomen and deltoid in a randomised, open-label, single-centre, single-dose, complete crossover trial. Each dose was followed by a 24-h euglycaemic clamp and 120-h pharmacokinetic blood sampling. The obtained pharmacokinetic/pharmacodynamic profiles were extrapolated to steady state by simulation using a pharmacokinetic/pharmacodynamic model. RESULTS: Total IDeg exposure [area under the IDeg serum concentration-time curve 0-120 h after a single dose (AUCIDeg,0-120h,SD)] and maximum serum concentration [maximum IDeg serum concentration after a single dose (C max,IDeg,SD)] were higher (6-7 and 23-27 %, respectively) following a single SC dose in the deltoid or abdomen, compared with the thigh, as also observed with other insulin preparations. No statistical difference was observed in these measures between deltoid and abdominal administration. No pronounced differences were observed in the glucose-lowering effect of IDeg [area under the glucose infusion rate (GIR) curve 0-24 h after a single dose (AUCGIR,0-24h,SD) and maximum GIR after a single dose (GIRmax,SD)] when injected in the thigh, abdomen or deltoid (AUCGIR,0-24h,SD 2,572, 2,833 and 2,960 mg/kg, respectively). Simulated mean steady-state pharmacokinetic and pharmacodynamic profiles supported a flat and stable IDeg exposure and effect regardless of injection region, with comparable total glucose-lowering effects [area under the GIR curve at steady state (AUCGIR,τ,SS)] between the thigh, abdomen and deltoid. CONCLUSIONS: These findings support administering IDeg SC in the thigh, upper arm or abdominal wall without affecting IDeg absorption or effect at steady state.

Distinct Prandial and Basal Glucose-Lowering Effects of Insulin Degludec/Insulin Aspart (IDegAsp) at Steady State in Subjects with Type 1 Diabetes Mellitus.

INTRODUCTION/AIM: Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of long-acting and short-acting insulin analogs. The primary objective of this study was to investigate the pharmacodynamic response of once-daily IDegAsp dosing in patients with type 1 diabetes. Pharmacokinetic response, as well as safety and tolerability, were assessed as secondary objectives. METHODOLOGY: This was a single-center, open-label, single-arm study. Twenty-two subjects received once-daily insulin degludec (IDeg) (0.42 U/kg) for five consecutive days [with separate bolus insulin aspart (IAsp) as needed for safety and glycemic control], to achieve clinical steady state of the basal component. On Day 6, they received a single injection of IDegAsp (0.6 U/kg, comprising 0.42 U/kg IDeg and 0.18 U/kg IAsp). Pharmacodynamic response was assessed using a 30-h euglycemic glucose clamp, with blood glucose stabilized at a target of 5.5 mmol/L. RESULTS: The glucose infusion rate profile showed a rapid onset of action and a distinct peak due to IAsp, followed by a separate, flat and stable basal glucose-lowering effect due to the IDeg component. Modeling data suggested that the pharmacodynamic profile of IDegAsp was retained with twice-daily dosing (allowing for coverage of two main meals daily). IDegAsp was well tolerated and no safety issues were identified in this trial. CONCLUSIONS: In conclusion, the IAsp component of IDegAsp has a fast onset of appearance and a peak covering the prandial phase, while the IDeg component has a flat and an evenly distributed pharmacokinetic profile over 24 h. IDegAsp is the first co-formulation of a basal insulin analog with an ultra-long duration of action and a mealtime insulin analog in a single soluble injection. These properties translate into clinically relevant benefits, including improved glycemic control and reduction in hypoglycemia.

Automated near-continuous glucose monitoring measured in plasma using mid-infrared spectroscopy.

OBJECTIVE: There are increasing calls for a precise, automated system to enable tight glycemic control and to avoid hypoglycemia in an intensive care unit setting. OptiScan Biomedical has developed a glucose monitor based on mid-infrared spectroscopy that withdraws blood samples (120 µl) and measures plasma glucose. The goal of this study was to validate the performance of the OptiScan Model 5000 over a wide range of glycemic levels in patients. RESEARCH DESIGN AND METHODS: Sixty people with type 1 (n = 18) or type 2 (n = 42) diabetes who were otherwise healthy were connected to OptiScanners. Their blood glucose concentrations were kept in a euglycemic, hypoglycemic (<75 mg/dl), and hyperglycemic (>180 mg/dl) range by intravenous administrations of insulin and glucose. OptiScanner venous blood samples were automatically withdrawn every 15 minutes. Reference measurements were done using the YSI 2300 glucose analyzer. RESULTS: The aggregate data points (1155 paired readings) were within International Organization for Standardization standards, with 98.6% of the glucose values within ±20% above 75 mg/dl and ±15 mg/dl below this value. A Clarke error grid analysis showed a total of 1139 points (98.6%) in zone A. Points outside of A exceeded the A zone boundary by an average of 4.3%. The r(2) was 0.99. The total coefficient for variance was 6.4%. CONCLUSIONS: These results show that the OptiScanner is highly accurate in healthy patients with diabetes across a wide range of glucose values. Mid-infrared spectroscopy may become the method of choice for highly accurate, high frequency, automated glucose measurements and may thus enable better glycemic control in critically ill patients.