1 Introduction
Due to a continuously growing elderly population, the number of elderly patients with diabetes who are being treated with insulin is also increasing [
1]. One implication of this is that it has become even more important to characterise the pharmacokinetic and pharmacodynamic properties of any new insulin product specifically in the elderly population.
Faster-acting insulin aspart (faster aspart) is insulin aspart in a new formulation with two added excipients (
l-arginine and niacinamide), which are both listed in the US Food and Drug Administration (FDA) inactive ingredient database as products approved for injection [
2]. L-arginine acts as a stabilising agent, while niacinamide results in faster initial absorption after subcutaneous administration. The aim of this formulation is to improve postprandial glucose control over current rapid-acting insulins. Clinical pharmacology studies have shown that faster aspart has an onset of appearance that is twice as fast and a twofold higher early insulin exposure than insulin aspart, which leads to more than 50% greater early glucose-lowering effect [
3‐
5]. In phase III trials conducted in subjects with type 1 (T1DM) and type 2 (T2DM) diabetes mellitus, postprandial glucose increments in standardised meal-tests were reduced with faster aspart versus insulin aspart [
6,
7]. As the majority of subjects in these previous studies with faster aspart were below 65 years of age, there is a need for specific knowledge about the pharmacological properties of faster aspart in the elderly population.
The objectives of the current study were to investigate the overall pharmacokinetic and pharmacodynamic characteristics of faster aspart in elderly subjects compared with those in younger adults, and to compare the early pharmacokinetic and pharmacodynamic properties between faster aspart and insulin aspart in elderly subjects using the same comparison in younger adults as a reference. The study was conducted in subjects with T1DM in order to be able to assess the glucose-lowering effect of the investigational insulins in a glucose clamp setting, without interference from endogenous insulin secretion.
2 Methods
2.1 Trial Design
This was a randomised, single-centre (Profil, Neuss, Germany), double-blind, two-period, crossover trial in elderly and younger adults with T1DM. The trial protocol was reviewed and approved by the local health authority (Bundesinstitut für Arzneimittel und Medizinprodukte) and by an independent ethics committee (Ärztekammer Nordrhein). The trial was performed in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice and relevant regulatory guidance on clinical trials in the elderly [
8‐
10]. Written informed consent was obtained before initiation of any trial-related activities. The trial was registered at ClinicalTrials.gov (trial identifier: NCT02003677).
2.2 Participants
Eligible subjects were elderly (≥65 years) or younger adult (18–35 years) men and women diagnosed with T1DM ≥12 months before being included in the trial who were treated with multiple daily insulin injections or continuous subcutaneous insulin infusion for ≥12 months (total daily insulin dose <1.2 (I)U/kg/day and total daily bolus insulin dose <0.7 (I)U/kg/day), with glycosylated haemoglobin (HbA1c) ≤9.5% (80 mmol/mol), body mass index (BMI) 18.5–28.0 kg/m2 and fasting C-peptide ≤0.3 nmol/L. Subjects were excluded if they had clinically significant concomitant diseases or clinically significant abnormal values in clinical laboratory screening tests, were smokers or were treated with any drugs that might interfere with glucose metabolism.
2.3 Procedures
The trial consisted of a screening visit (3–21 days before the first dosing visit), two dosing visits separated by 3–12 days of washout and a follow-up visit (7–21 days after the second dosing visit). At the dosing visits, subjects received single 0.2 U/kg dosing of faster aspart (100 U/mL; Novo Nordisk, Bagsværd, Denmark) or insulin aspart (NovoRapid®; 100 U/mL; Novo Nordisk) in a randomised sequence. Both trial products were provided in a blinded PDS290 pen-injector prefilled pen (Novo Nordisk) and were administered by subcutaneous injection into a lifted skin fold of the lower abdominal wall above the inguinal area.
At each dosing visit, subjects attended the clinic in the morning after an overnight fast. They were advised to avoid any physical exercise during the last 2 days before each dosing visit and to come to the clinic by car, taxi or public transport. Subjects received a single dose of trial product in a euglycaemic glucose clamp setting (ClampArt
®; Profil, Neuss, Germany) as previously described [
4]. The blood glucose (BG) clamp target level was 5.5 mmol/L (100 mg/dL) and the clamp lasted up to 12 h after dosing. The quality of the conducted clamps [
11] for each treatment and age group is presented in the Electronic Supplementary Material (Online Resource Table S1).
Blood samples for pharmacokinetic assessment were drawn within 2 min before dosing, then every 2 min from dosing until 20 min after dosing, every 5 min from 20 to 80 min, every 10 min from 80 min to 2 h, every 15 min from 2 to 3 h, and then at 3.5, 4, 5, 6, 7, 8, 10 and 12 h after dosing.
2.4 Assessments
Free serum insulin aspart concentrations (polyethylene glycol-precipitated) were measured by a validated insulin aspart-specific enzyme-linked immunosorbent assay. The glucose infusion rate (GIR) needed to keep the BG concentration at the clamp target level was recorded automatically every minute during the glucose clamp. Safety assessments included adverse events, local tolerability at the injection site, hypoglycaemic episodes, laboratory safety parameters, physical examination, vital signs and electrocardiogram. Hypoglycaemic episodes were defined as ‘confirmed’ when they were either ‘severe’ according to American Diabetes Association criteria, i.e. requiring third-party assistance [
12], or verified by a plasma glucose level of <3.1 mmol/L (56 mg/dL).
2.5 Endpoints
Endpoints evaluating onset of exposure and onset of glucose-lowering effect included the pharmacokinetic endpoints, onset of appearance (time from trial product administration until the first time serum insulin aspart concentration was greater than or equal to the lower limit of quantification [LLOQ; 10 pmol/L]), time to early 50% of maximum insulin aspart concentration (t
Early 50% Cmax) and time to maximum insulin aspart concentration (t
max), and the pharmacodynamic endpoints, onset of action (time from trial product administration until the BG concentration had decreased by at least 0.3 mmol/L [5 mg/dL] from baseline, where baseline was defined as the mean BG concentration from −5 to −1 min), time to early 50% of maximum GIR (t
Early 50% GIRmax) and time to maximum GIR (tGIRmax). Early exposure and early glucose-lowering effect were evaluated by deriving the early partial area under the concentration–time curve (AUC) values for serum insulin aspart (AUC for insulin aspart from time zero to 15 min [AUCIAsp,0-15 min], 30 min [AUCIAsp,0-30 min], 1 h [AUCIAsp,0-1 h], 1.5 h [AUCIAsp,0-1.5 h], and 2 h [AUCIAsp,0-2 h]) to assess pharmacokinetics and the AUCs for GIR (AUC for GIR from time zero to 30 min [AUCGIR,0-30 min], 1 h [AUCGIR,0-1 h], 1.5 h [AUCGIR,0-1.5 h], and 2 h [AUCGIR,0-2 h]) to assess pharmacodynamics. Overall exposure and glucose-lowering effect were evaluated by deriving the pharmacokinetic endpoints, total insulin aspart exposure (AUCIAsp,0-t) and maximum insulin aspart concentration (C
max), and the pharmacodynamic endpoints, total glucose-lowering effect (AUCGIR,0-t; primary endpoint) and maximum GIR (GIRmax).
In order to calculate onset of appearance and AUCIAsp,0-15 min, the insulin aspart concentration was imputed during the period from dosing of trial product until the time of the first insulin aspart concentration above LLOQ using compartmental modelling. This approach was also used for the initial part of the AUC in calculating all other AUCIAsp endpoints for consistency. AUCIAsp,0-t was derived by calculating the AUC until the time of last quantifiable insulin aspart concentration and then extrapolating until 12 h (the last pharmacokinetic sampling timepoint) based on the terminal slope. AUCGIR,0-t was calculated until time of last GIR observation >0. In order to ensure robust calculation of t
Early 50% GIRmax, GIRmax and tGIRmax, these endpoints were derived from LOESS smoothed GIR profiles (using a smoothing factor of 0.1). All other endpoints were derived from the raw profiles.
2.6 Statistical Analyses
No formal sample size calculation was performed. Before initiation of the trial, the number of subjects required to complete the trial was set to 40 (20 in each age group). With this sample size, assuming a total variance of log(AUC
GIR,0-t) of 0.17 [
3], the 95% confidence interval (CI) for the ratio of elderly/younger adults with respect to AUC
GIR,0-t would be expected to range from 0.77 to 1.30 times the estimated age group ratio. This was considered a sufficient precision for the current study. To account for potential dropouts, it was pre-planned to randomise 44 subjects (22 subjects per age group).
All statistical analyses were performed at a 5% significance level using all randomised subjects who received at least one dose of trial product. SAS® version 9.3 (SAS Institute, Cary, NC, USA) was used for all analyses.
Pharmacokinetic and pharmacodynamic endpoints were log-transformed (except for onset of appearance,
t
Early 50% Cmax,
t
max, onset of action,
t
Early 50% GIRmax,
tGIR
max and AUC
GIR,0-30 min) and analysed in a linear mixed model with age group, treatment, interaction between age group and treatment, and period as fixed effects and subject as a random effect. The variance of the random subject effect and the residual variance depended on the age group. The pharmacokinetic and pharmacodynamic properties were compared between faster aspart and insulin aspart for elderly and younger adults using treatment ratios and 95% CIs derived by back-transforming the model-based treatment differences and corresponding CIs. Treatment ratios and 95% CIs for endpoints analysed without log-transformation were calculated by Fieller’s method [
13]. To compare overall insulin exposure and overall glucose-lowering effect between elderly and younger adults for both faster aspart and insulin aspart, age group ratios and 95% CIs were calculated for AUC
IAsp,0-t,
C
max, AUC
GIR,0-t (statistical analysis of primary endpoint) and GIR
max from the same model as described above. For all analyses, a
p value for test of no interaction between age group and treatment was derived.
Safety endpoints were summarised by descriptive statistics for subjects receiving at least one dose of trial product.
4 Discussion
The main findings of the present study were the faster onset and greater early exposure and glucose-lowering effect observed with faster aspart versus insulin aspart in elderly subjects. The left shift of the pharmacokinetic and pharmacodynamic profiles of faster aspart versus insulin aspart in the elderly mirrors that seen in younger adults in the current study as well as in previous studies [
3‐
5], indicating that the ultra-fast pharmacological properties of faster aspart are preserved in elderly patients with diabetes.
The faster onset and greater early glucose-lowering effect of faster aspart than with insulin aspart indicate that faster aspart better mimics the insulin action seen in the healthy state in response to a meal. Thus, faster aspart may provide better mealtime coverage than current rapid-acting insulins. Indeed, in subjects with T1DM, superiority of faster aspart over insulin aspart in 2-h postprandial glucose excursion and a statistically significant difference in favour of faster aspart in 1-h postprandial glucose excursion were demonstrated in a meal-test [
6]. Likewise, in subjects with T2DM, the 1-h postprandial glucose excursion was statistically significantly reduced for faster aspart versus insulin aspart, while the treatment difference in 2-h postprandial glucose excursion in favour of faster aspart did not reach statistical significance [
7]. These two latter trials were conducted mainly in younger adults [
6,
7]. On the basis of the results of the current study we would hypothesise that similar improvements in postprandial glucose excursions would be achieved in elderly patients with diabetes. However, the potential for faster aspart to improve postprandial glucose control in elderly patients with diabetes still remains to be confirmed in further investigations.
The faster pharmacokinetic and pharmacodynamic properties of faster aspart may provide the option of post-meal administration, when necessary, thereby allowing the insulin dose to be more accurately adjusted to the actual food intake. This could be particularly useful in those elderly patients with cognitive impairment and/or irregular eating patterns. Potential benefits include improved control of postprandial glucose and, not least, a reduced risk of hypoglycaemia, which is considered a particularly serious problem and a barrier to optimal glycaemic control in elderly patients with diabetes [
15,
16]. In a standardised meal-test in elderly subjects with T2DM, insulin aspart administered at meal ingestion and regular human insulin administered 30 min before meal ingestion resulted in similar insulin and postprandial glucose profiles [
17]. Post-meal insulin lispro provided greater control of mean daily BG and a reduced incidence of hypoglycaemia and hyperglycaemia compared with regular human insulin administered 30 min before each meal in elderly subjects with T2DM living in nursing homes [
18]. Thus, it appears that current rapid-acting insulins allow for post-meal dosing, while still providing at least as good postprandial glucose control as regular human insulin administered pre-meal. In a similar manner, faster aspart administered 20 min post-meal has been compared with insulin aspart administered at mealtime in adult subjects with T1DM [
6]. The 2-h postprandial glucose increment was not statistically significantly different between post-meal faster aspart and mealtime insulin aspart, while the 1-h postprandial glucose increment was statistically significantly in favour of mealtime insulin aspart. The HbA
1c reduction seen during the 26-week treatment period was non-inferior, and overall rates of severe and confirmed hypoglycaemia were comparable, for post-meal faster aspart versus mealtime insulin aspart [
6]. Clinical evidence is needed to confirm the option of post-meal dosing of faster aspart in elderly patients with diabetes and the optimal time window for such administration.
We found a higher total exposure and
C
max of faster aspart in elderly than in younger adults. The same was seen for insulin aspart, although it was only statistically significant for total exposure. A similar trend has been observed in previous studies for the insulin degludec/insulin aspart combination, insulin degludec alone and for insulin detemir [
19‐
21], and would be in accordance with a reduced insulin clearance with increasing age [
22]. Importantly, we found comparable AUC
GIR,0-t and GIR
max in elderly and younger adults, as previously shown [
19]. The similar glucose-lowering effect in elderly and younger adults despite higher exposure in the elderly is in line with the well-known decrease in insulin sensitivity with aging [
23,
24]. In this context, it is also important to emphasise that the insulin dose should always be adjusted on an individual basis, depending on each patient’s needs. It follows that faster aspart should be considered safe also in elderly diabetes patients in terms of possible hypoglycaemia, although clinical data are needed to confirm this.
The clamp quality in the current study was high both in terms of precision and control deviation (Online Resource Table S1). Thus, the technical clamp issues experienced during the initial part of the study seem to have had no adverse impact on the quality of the results, as would also be expected since the affected data were excluded during a blinded review (see Sect. 3.1). In fact, the control deviation (i.e. the mean difference between the measured and the target BG concentration) was lower than in a previous series of experiments using the Biostator algorithm [
11]. Thus, optimising the algorithm as done during the present study may have contributed to reducing the control deviation.
Several review articles have emphasised the generally limited number of clinical trials investigating diabetes interventions in the elderly [
25‐
27]. Accordingly, to our knowledge, glucose clamp studies comparing the pharmacokinetic and pharmacodynamic properties of an insulin between elderly and younger adults and/or between two insulins in elderly subjects have only been conducted for a few insulin products [
19,
20,
28]. Therefore, a strength of the current study was the use of the euglycaemic glucose clamp technique to assess the pharmacodynamic properties. It is, however, also important to emphasise that an inherent limitation of the glucose clamp method is the experimental and standardised setting, which imposes some challenges in directly translating to clinical practice. Another limitation of the present study was the relatively few subjects per age group. Still, the number of subjects was higher than in similar previous studies in elderly subjects [
19,
20], and was sufficient to demonstrate statistically significant differences in pharmacokinetic and pharmacodynamic properties between faster aspart and insulin aspart in both age groups.
Acknowledgements
The authors would like to thank Theis Gondolf, MD, Novo Nordisk, for his review of and input into the manuscript and Carsten Roepstorff, PhD, CR Pharma Consult, Copenhagen, Denmark for providing medical writing support, which was funded by Novo Nordisk.
Compliance with Ethical Standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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