Use of fast‐acting insulin aspart in insulin pump therapy in clinical practice

Abstract Fast‐acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) containing the additional excipients niacinamide and L‐arginine. The improved pharmacological profile and greater early glucose‐lowering action of faster aspart compared with IAsp suggests that faster aspart may be advantageous for people with diabetes using continuous subcutaneous insulin infusion (CSII). The recent onset 5 trial was the first to evaluate the efficacy and safety of an ultra‐fast‐acting insulin in CSII therapy in a large number of participants with type 1 diabetes (T1D). Non‐inferiority of faster aspart to IAsp in terms of change from baseline in HbA1c was confirmed, with an estimated treatment difference (ETD) of 0.09% (95% CI, 0.01; 0.17; P < 0.001 for non‐inferiority [0.4% margin]). Faster aspart was superior to IAsp in terms of change from baseline in 1‐hour post‐prandial glucose (PPG) increment after a meal test (ETD [95% CI], −0.91 mmol/L [−1.43; −0.39]; P = 0.001), with statistically significant improvements also at 30 minutes and 2 hours. The overall rate of severe or blood glucose‐confirmed hypoglycaemia was not statistically significantly different between treatments, with an estimated rate ratio of 1.00 (95% CI, 0.85; 1.16). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and the 4‐week run‐in periods (4 vs 0). Experience from clinical practice indicates that all pump settings should be reviewed when initiating faster aspart with CSII, and that the use of continuous glucose monitoring or flash glucose monitoring, along with a good understanding of meal content and bolus type, may also facilitate optimal use. This review summarizes the available clinical evidence for faster aspart administered via CSII and highlights practical considerations based on clinical experience that may help healthcare providers and individuals with T1D successfully initiate and adjust faster aspart with CSII.

severe or blood glucose-confirmed hypoglycaemia was not statistically significantly different between treatments, with an estimated rate ratio of 1.00 (95% CI, 0.85; 1.16). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and the 4-week run-in periods (4 vs 0).
Experience from clinical practice indicates that all pump settings should be reviewed when initiating faster aspart with CSII, and that the use of continuous glucose monitoring or flash glucose monitoring, along with a good understanding of meal content and bolus type, may also facilitate optimal use. This review summarizes the available clinical evidence for faster aspart administered via CSII and highlights practical considerations based on clinical experience that may help healthcare providers and individuals with T1D successfully initiate and adjust faster aspart with CSII.

Continuous subcutaneous insulin infusion (CSII) using an insulin pump
is an increasingly popular treatment option for children and adults with type 1 diabetes (T1D). [1][2][3] In meta-analyses of randomized controlled trials, CSII is associated with improved glycaemic control and lower risk of severe hypoglycaemia compared with multiple daily injection (MDI) therapy. 4 CSII aims to mimic the physiological basal and prandial insulin profile, with basal infusion rates set to cover varying requirements during the night and between meals and useractivated bolus doses at mealtimes.
Most insulin pumps offer a range of pre-programmed bolus infusion types to provide coverage at mealtimes, including infusion of an entire bolus at once (standard bolus), infusion of small quantities over an extended period of time (delayed/extended bolus) or a combination of standard and delayed bolus (dual-/multi-wave). [5][6][7] Insulin pumps also have integrated bolus calculators that enable insulin dose calculation based on carbohydrate counting, personalized carbohydrate:insulin ratios, duration of insulin action and insulin sensitivity factors, and they allow insulin doses to be adjusted by one tenth of a unit or less, compared with one unit or half a unit with pen injectors.
Despite developments in insulin pump technology, there are a number of challenges in optimizing glycaemic control with CSII. These include optimization of basal and bolus infusion rates, selection of bolus type, time of meal bolus programming, variability of insulin action and type of insulin used. Calculation of appropriate insulin doses requires users to perform frequent blood glucose testing (selfmeasured blood glucose [SMBG]) at correct times or to use continuous glucose monitoring (CGM), 3,8,9 and to make accurate estimations of meal composition and carbohydrate content. 10,11 Conventional insulin pumps involve an external infusion set to deliver insulin from the insulin reservoir in the pump housing into the subcutaneous tissue, while recently developed patch pumps deliver insulin via a very short internal infusion set. 12 Pump failure, and infusion set malfunctions or occlusions, can cause unexplained hyperglycaemia, ketosis and diabetic ketoacidosis. 13 The infusion site and the duration of infusion site usage can also impact the rate of insulin absorption and, consequently, the glucose-lowering action. 14 In normal physiology, insulin is secreted very rapidly from the β-cell in response to, and even in anticipation of, a meal. Despite advances in insulin formulations, subcutaneously administered insulins have a delayed onset and a longer duration of action compared with endogenously secreted insulin. A recent study found a positive correlation between time-to-peak insulin action and HbA1c level in studies of closed-loop insulin delivery and sensor-augmented pump therapy, indicating the need for insulins with rapid and consistent absorption properties that are more able to reproduce physiological insulin responses. 15 Current rapid-acting insulin analogues (RAIAs)insulin aspart (IAsp), insulin lispro and insulin glulisinehave faster absorption kinetics than regular human insulin; 16 however, post-prandial glucose (PPG) control with pump therapy remains limited by the pharmacokinetics of RAIAs. 17 A new generation of ultra-fast-acting insulins, such as BioChaperone Lispro, 18,19 treprostinil lispro 20 and fast-acting insulin aspart (faster aspart), is under development. Faster aspart is the first of these to be approved for pump use in adults with T1D and type 2 diabetes (T2D) and it is now available in several countries. This review summarizes the available clinical data for faster aspart administered via CSII and highlights some practical considerations for its use in insulin pumps based on this evidence, as well as observations from clinical practice.

| Fast-acting insulin aspart (faster aspart)
Faster aspart is a novel formulation of IAsp containing the additional excipients niacinamide and L-arginine. 21 This novel formulation builds on the safety studies of conventional IAsp, 22,23 and both excipients are listed by the US Food and Drug Administration (FDA) as "generally recognized as safe" (GRAS). 24 Niacinamide mediates faster initial absorption into the bloodstream by both increasing the initial abundance of IAsp monomers in the subcutaneous depot, and by mediating a transient, local vasodilatory effect; 25 L-arginine functions as a stabilizing agent.
In a pooled analysis of six clinical studies in adults with T1D, faster aspart administered via subcutaneous injection demonstrated an accelerated pharmacological profile compared with IAsp. 21,26 Faster aspart had an approximately 5-minute earlier onset of appearance in the circulation, an approximately two-fold higher early insulin exposure and an approximately 74% greater early glucose-lowering effect within the first 30 minutes compared with IAsp. 26 In addition, offset of exposure and glucose-lowering effect occurred 12-14 minutes earlier with faster aspart than with IAsp. Similar pharmacological properties following subcutaneous injection have been observed in elderly adults and in a Japanese population, 27,28 as well as in children and adolescents with T1D. 29 When delivered via CSII, the left-shift in the pharmacological profile of faster aspart vs IAsp appears to be even greater compared with that seen after subcutaneous injection ( Figure 1). In adults with T1D using CSII, faster aspart demonstrated an approximately three-fold higher early insulin exposure and an approximately 100% greater glucoselowering effect within the first 30 minutes compared with IAsp. 30 In addition, offset of exposure and offset of glucose-lowering effect occurred 35 and 24 minutes earlier, respectively, with faster aspart than with IAsp. The reason for the differences between subcutaneous and CSII administration is not completely understood, and comparisons across trials should always be undertaken with caution; however, one hypothesis is that the continuous supply of niacinamide in a CSII setting further augments the rate of insulin monomer dissociation, thereby further increasing the early absorption rate of faster aspart compared with conventional IAsp. It is also possible that the smaller size of the CSII subcutaneous insulin depot, compared with a bolus injection, contributes to the accelerated kinetics of faster aspart versus IAsp.     lacking. Herein, we highlight important considerations that may aid healthcare providers (HCPs) and individuals with diabetes in successfully initiating and adjusting faster aspart with CSII. A number of these considerations will probably also apply to other ultra-fast-acting insulins currently in development.

| Closed-loop automated insulin delivery systems
As in the onset 5 trial, a 1:1 unit dose conversion is recommended when switching to faster aspart. However, while pump settings may have been ideal for the previously used insulin, given the difference in pharmacology, a review of and guided change in all pump settings should be expected over the weeks and months following the switch. Differences in bolus delivery between different insulin pumps should also be taken into consideration, as these can affect the pharmacological characteristics of mealtime insulin 44 and may also influence the "insulin on board" or active insulin estimation, that is, the residual glucose-lowering activity from prior boluses, and therefore, the correction bolus dosing.
Because of the accelerated absorption kinetics of faster aspart, bolus dosing will need to be addressed to reduce the risk of early post-prandial hypoglycaemia or late post-prandial hyperglycaemia.
Early post-prandial hypoglycaemia is uncommon, but it may become an issue after unexpectedly delayed meals or meals with a high fat content, errors in carbohydrate counting, or in patients with gastroparesis. Data suggest that administration of a pre-prandial bolus of ultra-rapid-acting insulin 15 minutes before a meal, compared with immediately before, can improve post-prandial hyperglycaemia. 45 While this was not examined in the onset 5 trial, clinical experience suggests that pre-meal bolus dosing can be beneficial for pump users with faster aspart, especially when consuming food with a high glycaemic index. Adjustments to the basal insulin dose, potentially using a basal rate test, will also need to be taken into consideration for optimal use of faster aspart, 46 although HCPs should be aware that some pump users will not be accustomed to changing basal rate parameters without support from their treatment team.
Pump users should monitor BG adequately and may need to increase the frequency of SMBG testing to enable optimization. The use of CGM or flash glucose monitoring (FGM) could enable optimization of dosing for each individual user when switching to faster aspart.
If long-term use of CGM or FGM is not possible, short-term use over 8-12 weeks would probably be helpful. Monitoring the "insulin on board"/active insulin function of the pump could help pump users understand and tailor their dosing needs.
A good understanding of meal content and the glycaemic index is probably important for pump users to fully benefit from the effect of faster aspart. Although the use of faster aspart in the context of highor low-glycaemic index meals has not been addressed in clinical trials, there may be a need for different bolus types, such as a delayed/extended bolus with larger meals or a dual-or multi-wave bolus for high-fat and high-protein meals ( Figure 2). [47][48][49] As a starting point for high-fat and high-protein meals, 30% of the total insulin dose can be administered immediately and 70% administered with a delay over the 2-4 hours following the meal. It should also be noted that more insulin than that calculated by carbohydrate counting alone may be needed. 49,50 The occurrence of a burning sensation around the infusion site has been reported in some individuals using faster aspart in clinical practice. Some users also report the necessity of changing their infusion set more frequently after switching to faster aspart to avoid hyperglycaemia, and others have found that correction doses are not as effective as expected. There are likely to be other, currently unknown, factors involved in determining the success of treatment with faster aspart using CSII, and HCPs may find that improvements in glycaemic control are seen in some users, but not necessarily all.

| SUMMARY
Use of faster aspart in insulin pump therapy provides potential benefits for glycaemic control. The improved PK/PD profile of faster aspart compared with that of IAsp suggests that faster aspart may be advantageous for individuals with diabetes using CSII. While the large, double-blind onset 5 trial demonstrated that faster aspart is effective in glycaemic control, superiority of faster aspart over IAsp in terms of HbA1c reduction was not confirmed, although meal test and CGM results suggest that faster aspart is especially beneficial for PPG control. Experience from clinical practice indicates that initiating faster aspart with CSII should not be viewed as a simple switch of insulin. All pump settings will need to be reviewed and tailored to the individual patient. The use of CGM or FGM, along with a good understanding of meal content and bolus type, may also facilitate optimal use of faster aspart with CSII. There is currently limited evidence concerning the clinical use of faster aspart with CSII, and further studies are required to maximize its potential benefits in pump therapy.

ACKNOWLEDGMENTS
The authors are grateful to Helen Parker, PhD and Erin Slobodian of Consideration should be given to matching the type of bolus insulin administered via a pump with the expected glucose profile of a meal.
Healthcare plc, for medical writing and editorial assistance in the