Clinical considerations for use of insulin degludec/insulin aspart in Japanese patients

ABSTRACT

Introduction: Co-formulation of basal and bolus insulin components provides a simpler regimen for patients with type 2 diabetes than separate basal–bolus treatment. However, conventional premixed insulin products include a suboptimal protaminated basal component that requires resuspension prior to injection. Insulin degludec/insulin aspart (IDegAsp) is the first soluble co-formulation of a basal insulin with an ultra-long duration of action (IDeg) and a rapid-acting bolus insulin (IAsp) in a single injection.

Areas covered: In this review, the authors summarize findings from pre-clinical studies and the clinical trial program and provide guidance for the initiating and switching of IDegAsp in different patient populations. Pharmacodynamic analyses have revealed a rapid onset of action and distinct peak (IAsp), followed by a separate, flat and stable basal effect (IDeg component). Phase 3 studies have demonstrated the efficacy and safety of IDegAsp, with greater glycemic improvements than basal-only therapy in international and Japanese type 2 diabetes populations. IDegAsp also results in reduced insulin dose requirements and lower rates of hypoglycemia than premixed insulin.

Expert opinion: IDegAsp provides a simple and effective insulin regimen in appropriately selected Japanese patients, with the flexibility to suit individual needs. The benefits of IDegAsp over conventional insulin regimens might help tackle clinical inertia with insulin intensification.

KEYWORDS:

• (min. 4 required): hypoglycemia
• insulin degludec
• Japanese
• IDegAsp

1. Introduction

Diabetes is a public health concern in Japan. In 2015, it was estimated that 7.2 million people in the country have diabetes, and a further 11.9 million live with impaired glucose tolerance [1].

Type 2 diabetes (T2D) is the most common form of the disease in Japan, with type 1 diabetes (T1D) occurring at a lower rate. T2D is characterized by a progressive decline in beta-cell function and glycemic control, often requiring treatment with antihyperglycemic therapies. To achieve and maintain targets, treatment typically progresses from diet and exercise therapy to oral glucose-lowering monotherapy, to combination treatment, and eventually to insulin therapy [2–4].

According to guidelines from the Japanese Diabetes Society, an oral glucose-lowering agent should be initiated if adequate diet and exercise therapy fails to achieve glycemic control within 2–3 months (for most patients, this is defined as glycated hemoglobin [HbA_1c] <7.0%) [5]. Insulin therapy should be given to patients who do not reach their glycemic goal with diet and exercise therapy and with oral glucose-lowering agents [5].

Interventions that address postprandial hyperglycemia become increasingly important as diabetes progresses and postprandial glucose control needs to be more directly addressed [6]. This is often achieved by directly supplementing the prandial insulin response with rapid-acting insulins, as part of a premixed therapy [7,8].

Despite this guidance, treatment intensification to include insulin therapy is often delayed in normal clinical practice across the globe [3,9,10]. Many reasons have been suggested for this delay, including preconceptions among some physicians and patients regarding the increased burden of multiple injections and blood glucose monitoring, the complexity of multi-medication regimens, and concerns about the risks of hypoglycemia and body weight gain [3,4].

Co-formulation of basal and bolus insulin components could mitigate some of these issues, in particular by providing a simpler regimen that gives both basal and mealtime coverage with fewer injections than basal-bolus therapy [11].

Current premixed insulins contain both fast- and intermediate-acting components, using intermediate-acting insulins that are protaminated to delay absorption. However, they do not provide the basal coverage seen with the newer long-acting basal insulins [12]. The Treating to Target in Type 2 Diabetes (4-T) compared the 3-year efficacy and safety of different insulin regimens (prandial, biphasic, and basal) and demonstrated significantly higher median rates of hypoglycemia (5.7, 3.0, and 1.7 events per patient per year, respectively) and a greater increase in mean body weight with prandial or biphasic insulin compared with basal insulin. It is possible that the extent of this relative disadvantage was increased by the suboptimal pharmacokinetic/pharmacodynamic profile of the conventional premix insulin included in this study [6]. In addition, resuspension is needed prior to injection of these premixed formulations, increasing complexity of the regimen for the patient and potentially resulting in variability in dosing and subsequent risk of hypoglycemia.

With insulin glargine (IGlar) and insulin detemir (IDet), the first-generation of long-acting insulin analogs, co-formulation with fast-acting insulin analogs has not been possible due to physicochemical incompatibility or the formation of hybrid hexamers, respectively, leading to unwanted changes in pharmacokinetic (PK) and pharmacodynamic (PD) profiles [13–16].

Insulin degludec/insulin aspart (IDegAsp) is the first soluble co-formulation of a basal insulin with an ultra-long duration of action (insulin degludec [IDeg]; 70%), and a rapid-acting bolus insulin (insulin aspart [IAsp]; 30%), in a single injection. It has been available in Japan since December 2015. This review provides guidance on the use of IDegAsp in clinical practice in Japan, focusing primarily on patients with T2D. Guidance on the use of IDegAsp from an international perspective has been published elsewhere [17].

2. Structure and PK/PD properties

The molecular structure of IDeg allows it to be co-formulated with IAsp in the presence of zinc and phenol, without the risk of formation of hybrid hexamers [18]. Hence, in solution, the two insulin components exist separately and in a stable form – IDeg as dihexamers and IAsp as hexamers. Upon subcutaneous injection, IDeg dihexamers self-associate to form a stable depot of multi-hexamers, from which IDeg monomers dissociate slowly and continuously – giving IDeg its long duration of action. Meanwhile, IAsp hexamers dissociate rapidly to monomers that are readily absorbed into the circulation, hence the fast onset of action and suitability for bolus insulin supplementation at meal times (Figure 1) [18].

Figure 1. Mechanism of action of the insulin degludec/insulin aspart co-formulation, IDegAsp. In the pharmaceutical preparation, soluble di-hexamers are formed by the IDeg component at neutral pH, whereas IAsp remains as distinct hexamers. Upon injection, IDeg di-hexamers immediately form stable multi-hexamers in the subcutaneous tissue from which IDeg monomers slowly and continuously dissociate. IAsp hexamers quickly dissociate to monomers and are therefore rapidly absorbed into the circulation. Adapted from Haahr et al. 2017 [19].

IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart.

In contrast with conventional premixed insulins, the solubility of the IDegAsp co-formulation removes the need for resuspension prior to injection. IDegAsp also offers a simple dosing regimen, with fewer injections being required than with traditional basal-bolus therapy [11].

The basal component of IDegAsp, IDeg, has a half-life of 25 h and four-times lower variability in glucose-lowering effect compared with IGlar [20,21]. These properties contribute to the flat, stable, and ultra-long duration of action of IDeg, demonstrated in both Caucasian and Japanese patients [14,20–22].

When IDeg is co-formulated with IAsp, the glucose infusion rate profile shows a rapid onset of action and distinct peak due to the IAsp component, followed by the separate, flat, and stable basal effect of the IDeg component (Figure 2). These discrete prandial and basal effects of the two components have been demonstrated both in Caucasian [23] and in Japanese subjects (Figure 3) [24].

Figure 2. Mean glucose infusion rate profile of once daily IDegAsp 0.6 U/kg administered at steady state in patients with type 1 diabetes. Reproduced from [23].

IDegAsp, insulin degludec/insulin aspart.

Figure 3. Mean glucose infusion rate profiles of IDegAsp 0.5 U/kg after single dose and simulated to once daily steady state in Japanese patients with type 1 diabetes. Adapted from Haahr et al. 2016 [24] with permission of John Wiley and Sons.

IDegAsp, insulin degludec/insulin aspart.

Modeling data have suggested that the PD profile of IDegAsp is also retained with twice-daily dosing in Japanese subjects, allowing for appropriate insulin coverage across two main meals per day, if required (Figure 4) [24].

Figure 4. Mean glucose infusion rate profile of IDegAsp 0.25 U/kg per dose simulated to twice-daily steady state in Japanese patients with type 1 diabetes [24] with permission of John Wiley and Sons.

IDegAsp, insulin degludec/insulin aspart.

Owing to the ultra-long duration of action of IDeg, concerns have been raised that ‘stacking’ (characterized by excessive accumulation of insulin in the circulation) could occur. However, a recent analysis of PK data from five separate randomized trials revealed that steady-state plasma levels of IDeg are reached within 2–3 days of any dose change, including initiation of the insulin [25]. After this time, accumulation ceases, with the 24-h elimination rate equaling the 24-h absorption rate [25].

2.1. Clinical evidence

In the following section, the Japanese trials of IDegAsp are reviewed; along with two additional (non-Japanese) trials that provide additional information that is of clinical relevance. The full global trial program has been reviewed elsewhere [17]. A summary of the phase III clinical trials of IDegAsp in T1D and T2D discussed below is presented in Table 1 [26,28–30,35].  

Table 1. Summary of phase III clinical trials of insulin degludec/insulin aspart (IDegAsp) in patients with type 1 and type 2 diabetes. Adapted from Kumar et al. 2016 [17] with permission of John Wiley and Sons.

Reference	Study design	Patient population	Number of Japanese subjects included	Dosing of IDegAsp	Comparator	HbA1c difference (95% CI)	Hypoglycemia difference	Weight (Kg)	Insulin dose difference
Hirsch et al. [26]	26-week, open-label, randomized, treat-to-target	T1D (n = 548)	n = 0	Once daily at any meal	IDegAsp + IAsp (at meal-times) vs. IDet + IAsp (at meal-times) 2:1	–0.05 (0.18; 0.08)	Overall 0.91 (95% CI 0.76–1.09), P = NS Nocturnal confirmed: 37% lower IDegAsp vs. IDet + IAsp P < 0.05	+2.3 (IDegAsp) and +1.3 (IDet), respectively (P < 0.05)	13% lower with IDegAsp vs. IDet (P < 0.0001)
Kumar et al. [27]	52-week, open-label, randomized, treat-to-target	Insulin-naive T2D (n = 530)	n = 0	Once-daily with morning meal at same dosing time each day (starting dose not specified)	IDegAsp once-daily vs. IGlar once-daily 1:1	–0.08 (–0.26; 0.09), P = NS (non-inferiority confirmed)	Overall 1.86 (95% CI 1.42; 2.44), P < 0.0001 Nocturnal 0.25 (95% 0.14; 0.47), P < 0.0001	Δ(IDegAsp-IGlar) –1.60 (95% CI 0.84; 2.36), P < 0.0001	IDegAsp vs. IGlar 70 U vs. 62 U
Onishi et al. [28]	26-week, open-label, randomized, treat-to-target	Insulin-naïve T2D (n = 296) (Japanese)	n = 296	Once daily, initiated at 10 U	IDegAsp vs. IGlar 1:1	–0.28 (–0.46; – 0.10), P < 0.01	Overall 0.73 (95% CI 0.50; 1.08), P = NS Nocturnal: 0.75 (95% CI 0.34; 1.64) P = NS	+0.7 (IDegAsp) + 0.7 (IGlar)	0.41 U/kg (IDegAsp) 0.41 U/kg (IGlar)
Kaneko et al. [29,30]	26-week, open-label, randomized, treat-to-target	Insulin-experienced T2D (n = 424) (Asian)	n = 178	Twice daily with breakfast and main evening meal	IDegAsp vs. BIAsp 30 2:1	0.05 (–0.10; 0.20)	Overall 1.00, (95% CI 0.76; 1.32), P = NS Nocturnal: 0.67 (95% CI 0.43; 1.06), P = NS Severe: 1.30 (95% CI 0.24; 7.03); P = NS	Δ(IDegAsp-BIAsp 30) –0.38 (95% CI – 0.96; 0.21) P = NS	IDegAsp vs. BIAsp 30 0.79 (95% CI 0.73; 0.85), P < 0.0001
Fulcher et al. [31]	26-week, open-label, randomized, treat-to-target	Insulin-experienced T2D (n = 447)	n = 0	Twice daily with breakfast and main evening meal	IDegAsp BID vs. BIAsp 30 BID (1:1)	–0.03 (–0.18; 0.13), P = NS non-inferiority confirmed	Overall 0.68 (95% CI 0.52; 0.89), P = 0.0049 Nocturnal 0.27 (95% CI 0.18; 0.41), P < 0.0001	Δ(IDegAsp-BIAsp 30) –0.62 (95% CI – 1.15; – 0.10), P < 0.05	IDegAsp vs. BIAsp 30 0.89 (0.83; 0.96), P = 0.002
Christiansen et al. [32]	Combined analysis of two phase IIIa trials [29,31]	Insulin-experienced T2D Global vs. Asian population (n = 868)	Asian population (Japan, Hong Kong, Malaysia, South Korea and Taiwan) n = 422	Twice daily with breakfast and the main evening meal	IDegAsp vs. BIAsp 30	0.00 (–0.11; 0.10), P = NS	IDegAsp vs. BIAsp 30: Overall: RR 0.81 (95% CI 0.67; 0.98), P = 0.03 Nocturnal: 0.43 (95% CI 0.31; 0.59), P < 0.0001 Severe: 0.61 (95% CI 0.26; 1.45), P = 0.27	Δ(IDegAsp-BIAsp 30) –0.50 (95% CI – 0.88; 0.11), P = 0.012	IDegAsp vs. BIAsp 30 0.84 (0.80; 0.89), P < 0.0001
Rodbard et al. [33]	26-week, randomized, multinational, treat-to-target	Insulin-experienced T2D (n = 274)	n = 0	IDegAsp twice daily (breakfast or lunch and evening meal)	IDegAsp twice daily vs. IDeg + IAsp 2–4 times daily 1:1	0.18 (–0.04; 0.41), P = NS (non-inferiority not met)	Overall 0.81 (95% CI 0.61; 1.07), P = NS Nocturnal: 0.80, (95% CI 0.50; 1.29), P = NS	Δ(IDegAsp-IDeg+IAsp) –1.04 (95% CI – 1.99; 0.10), P < 0.05	IDegAsp vs. IDeg+IAsp 0.88 (95% CI 0.78; 1.00), P < 0.05
Kumar et al. [34]	26-week, open-label, randomized, treat-to-target	Insulin-experienced T2D (n = 465)	n = 0	Once-daily with main evening meal/largest meal at same dosing time each day	IDegAsp once-daily vs. IGlar once-daily 1:1	–0.03 (–0.20; 0.14), P = NS (non-inferiority confirmed)	Overall 1.43 (95% CI 1.07; 1.92), P < 0.05 Nocturnal 0.80 (95% CI 0.49; 1.30), P = NS	Δ(IDegAsp-IGlar) –0.33 (95% – 0.17; 0.83), P = NS	IDegAsp vs. IGlar 60 U vs. 60 U

BIAsp 30: biphasic insulin aspart 30; CI: confidence interval; HbA_1c: glycosylated hemoglobin; IAsp: insulin aspart; IDeg: insulin degludec; IDegAsp: insulin degludec/insulin aspart; IDet: insulin detemir; IGlar: insulin glargine; NS: not significant; RR: rate ratio; T1D: type 1 diabetes; T2D: type 2 diabetes. Δ(IDegAsp-BIAsp 30) = estimated treatment difference with IDegAsp vs. BIAsp 30; Δ(IDegAsp-IDeg+IAsp) = estimated treatment difference with IDegAsp vs. IDeg+IAsp.

 

2.1.1. Type 1 diabetes

IDegAsp was assessed in a 26-week, randomized, open-label, treat-to-target phase III trial [26]. No Japanese subjects were enrolled. In this study, IDegAsp was given once daily at the main meal with IAsp given at other meals, and compared with a basal–bolus regimen of IDet once or twice daily plus IAsp at meal times, in patients with T1D. IDegAsp was shown to be non-inferior to the basal–bolus regimen in HbA_1c reduction, and was associated with a significantly lower (13%; P < 0.0001) total daily insulin dose [26]. In the 26-week extension phase of this study, the rate of overall confirmed hypoglycemia was lower with IDegAsp (31.8 episodes/person-year of exposure [PYE]) compared with the basal-bolus regimen (36.7 episodes/PYE) [36] and the rate of nocturnal confirmed hypoglycemia was significantly lower with IDegAsp compared with the basal–bolus regimen (3.1 vs. 5.4 episodes/PYE, respectively; P < 0.05).

2.1.2. Type 2 diabetes

Several phase III studies of IDegAsp have been conducted in patients with T2D from around the world.

Some of these studies included subjects from Japan. In particular, an open-label, treat-to-target phase III study of IDegAsp recruited only Japanese patients (n = 296) [28]. Subjects were insulin-naïve adults with T2D that was poorly controlled despite treatment with one or more oral agents, randomized 1:1 to once-daily injections of IDegAsp or IGlar 100 units/mL (U100) for 26 weeks, both ± ≤2 oral antidiabetic treatments. While mean fasting plasma glucose (FPG) levels were similar between groups, IDegAsp demonstrated superior HbA_1c reduction compared with IGlar U100 (estimated treatment difference, ETD; IDegAsp-IGlar: −0.28% points [95% CI −0.46; −0.10], P < 0.01) and a significantly lower end of trial mean HbA_1c (IDeg, 7.0% vs. IGlar, 7.3%). Although not statistically significant, IDegAsp was associated with numerically lower rates of overall confirmed and nocturnal confirmed hypoglycemia compared with IGlar (estimated rate ratios: 0.73 [95% CI: 0.50, 1.08] and 0.75 [95% CI: 0.34, 1.64], respectively). Mean daily insulin doses were similar between groups [28]. The authors concluded that IDegAsp provided superior glycemic control, with similar FPG levels and insulin doses and numerically lower rates of overall and nocturnal hypoglycemia, compared with IGlar U100.

A randomized, open-label, treat-to-target phase III study of IDegAsp twice daily versus premixed insulin (biphasic insulin aspart 30 [BIAsp 30]) in 424 insulin-experienced Asian patients with T2D included 178 Japanese subjects [29,30]. In this trial, IDegAsp showed non-inferiority in mean change in HbA_1c compared with BIAsp 30, and yielded significantly greater reductions in FPG (ETD: –1.06 mmol/L [95% CI: −1.43, −0.70] P < 0.001). The final mean daily insulin dose was also significantly lower with IDegAsp (0.79 U/kg vs. 0.99 U/kg, estimated rate ratio 0.79 [95% CI 0.73, 0.85] P < 0.0001). Rates of overall confirmed hypoglycemia were similar between treatments [29].

In a sub-analysis of the Japanese population from this study [35], similar reductions were observed when comparing change from baseline HbA_1c with IDegAsp twice daily (−1.40%) and BIAsp twice daily (−1.29%), with an estimated treatment difference of −0.13% (95% CI: −0.31, 0.04). Overall confirmed hypoglycemia rates were similar between the treatment groups; the nocturnal confirmed hypoglycemia rate was lower with IDegAsp twice daily versus BIAsp 30 twice daily (estimated rate ratio 0.44 [95% CI 0.20, 0.99]). No severe hypoglycemic episodes were reported in either group [35].

To further characterize the efficacy and safety profile of IDegAsp twice daily, a recent meta-analysis combined data from two studies (one global study and one Asian study) with similar trial design in the global phase III development program [32]. This analysis showed that, in insulin-experienced patients with T2D, IDegAsp provided similar improvements in glycemic control versus BIAsp 30, with a significantly lower risk of overall confirmed and nocturnal confirmed hypoglycemia (estimated rate ratios: 0.81 [95% CI: 0.67, 0.98] P = 0.03 and 0.43 [95% CI: 0.31, 0.59] P < 0.0001, respectively).

A phase III study of 274 (non-Japanese) patients with T2D, inadequately controlled with basal insulin, found that intensification with IDegAsp twice daily or with IDeg once daily plus IAsp 2–4 times daily both effectively improved glycemic control [33]. While there was no significant difference between the treatment groups, non-inferiority criteria were not met. Hence, IDegAsp may be an alternative for Japanese patients in whom 3–5 injections daily is not suitable.

2.2. Japanese clinical guidelines

According to Japanese guidelines for the treatment of diabetes, a glycemic target of HbA_1c <7.0% is recommended for suitable patients across all age groups, to ensure prevention of diabetic complications [5]. However, the goals for glycemic control should always be individualized based on the patient’s age, duration of diabetes, complications status, and risk of hypoglycemia, as well as the support system available to address any complications that arise. An HbA_1c goal of 6.0% may represent the best target for ensuring glucose normalization, and can be used in appropriate patients; meanwhile, a target of 8.0% may serve as a better goal in some patients when intensive therapy is not feasible, for example due to elevated hypoglycemia risk [5]. Higher targets may, for example, be recommended for elderly patients with additional health conditions and who are treated with anti-diabetes medications carrying a risk of severe hypoglycemia (e.g. insulins or sulfonylureas) – an HbA_1c goal of 6.5–7.5% is recommended for those aged between 65 and 75 years, increasing to 7–8% for those over 75 years of age [5].

Insulin therapy should be considered in patients who have not achieved their individualized glycemic target despite diet and exercise therapy and glucose-lowering agents [5].

2.3. Clinical use of IDegAsp in Japan

2.3.1. Administration

In patients with T2D, IDegAsp can be administered once or twice daily. In T1D, it should be given once daily, in combination with bolus insulin at the remaining meals.

IDegAsp comes as a 100 U/mL solution in a pre-filled pen requiring no resuspension prior to injection. When used in a once-daily regimen, IDegAsp is given just before the main meal, which should be the same meal every day. Dose timing should be adjusted if the dietary habits of the patient change [37]. Physicians should consider that the ‘main meal’ refers to the meal with the highest postprandial glucose level, i.e. the highest carbohydrate load. In a twice-daily regimen, IDegAsp is given just before breakfast and the evening meal.

2.3.2. Initiation of IDegAsp treatment in T2D

As with all diabetes treatments, IDegAsp should be dosed on an individual basis [5,37]. The decision on whether to initiate IDegAsp as a once- or twice-daily therapy should be made by the treating physician, taking into account the individual circumstances of the patient, such as their personal wishes and normal eating pattern.

According to the Japanese label, when initiating treatment with IDegAsp, 4–20U are generally given subcutaneously [37]. For most patients, we recommend a starting dose of 10 U, as per clinical trials (Table 1) [28,38], followed by individual dosing adjustments. Close glucose monitoring is recommended during, and in the weeks following, the initiation of IDegAsp [37].

2.3.3. Switching from other insulin products to IDegAsp in T2D

As shown in clinical trials, IDegAsp can provide clinical benefits for patients who previously received premixed insulin, by reducing the risk of hypoglycemia and removing the need for resuspension [32]. For patients whose T2D was previously uncontrolled on basal insulin, IDegAsp can provide improvements in glycemic control without an increased risk of hypoglycemia (Table 1) [34].

2.3.4. Basal insulin

Generally, a 1:1 switch is recommended from a patient’s previous basal insulin [37]. However, dose reduction should be considered if blood glucose level is low or the patient is experiencing recurrent hypoglycemia. An increase in insulin dose could be considered if the patient is switching from IDeg, providing that the physician considers this to be safe and advantageous to the patient.

In a 26-week, open-trial, global phase III trial, 465 patients inadequately controlled on basal insulin were randomized to receive either IDegAsp or IGlar, both administered once-daily; the main trial findings are summarized in Table 1. Notably, a post hoc analysis of this trial showed that switching from a once-daily regimen of high dose basal insulin (>40 U/day) to IDegAsp once daily is not associated with an increased rate of hypoglycemia [34]. However, sound clinical judgment is required to ensure that the bolus component of IDegAsp is suitable for the carbohydrate content of the meal that it will cover. When switching insulins, close monitoring of glycemic control and insulin dose is important and adjustments to oral agents should be considered.

2.3.5. Premix insulin

When switching from premix insulin twice daily, a dose reduction of 10–20% should be considered. The dose should be adjusted depending on the condition of the patient [37]. For example, a higher dose reduction could be considered if FPG/HbA_1c is low or there is recurrent hypoglycemia.

When switching from once-daily to twice-daily dosing of IDegAsp, consideration should be given to ensuring the bolus dose is appropriate for the carbohydrate content of the meal it will cover.

2.3.6. IDegAsp treatment in T1D

For insulin-naïve patients with T1D, a starting dose of between 0.2 and 0.4 U IDegAsp per kg of body weight is recommended in the US prescribing information [39]. When switching from other insulin regimens, the total daily dose should be initiated at the same dose as the dose of previous insulin [26,37,40]. The Japanese label also states that IDegAsp should be initiated with careful consideration of each patient’s condition; in the summary of product characteristics and clinical trials, the starting dose of IDegAsp is 60–70% of the previous total daily insulin requirements in combination with rapid-acting insulin at the remaining meals followed by individual dosage adjustments [26,40]. Both the IDegAsp and prandial insulin components should be administered before meals [26,37,40]. There are relatively fewer studies of IDegAsp use in patients with T1D, but findings from a 26-week, phase III, open-label trial comparing IDegAsp given once daily with a standard basal–bolus regimen in 548 patients with T1D revealed that IDegAsp resulted in non-inferior glycemic control and a reduced risk of nocturnal hypoglycemia with fewer injections versus basal-bolus therapy [26] (Table 1).

2.3.7. Titration of IDegAsp

The IDegAsp dose should be adjusted appropriately depending on individual patient symptoms and plasma glucose test findings. In the phase III clinical trial conducted in Japan, the IDegAsp dose was titrated to target self-measured plasma glucose (SMPG) levels of 4.0–4.9 mmol/L (72–90 mg/dL), according to mean pre-breakfast (once daily) and pre-breakfast and pre-evening meal (twice daily) plasma glucose values over the preceding 3 days [28]. The same SMPG target was used in the multi-Asian phase III trial, with insulin titrated according to mean pre-breakfast and mean pre-main evening meal glucose values from the preceding 3 days [29].

In the context of daily clinical practice, the dose of IDegAsp should always be tailored to the needs of the individual patient. The suggested target FPG level is 80–100 mg/dL (4.4–5.5 mmol/L), with 1–2 U adjustments in patients who are above or below that level, based on several SMBG readings per week.

It should be remembered that as 2–3 days are required for the IDeg component to reach steady state [25], some degree of hyperglycemia can occur in the first 1–2 days following initiation of IDegAsp.

3. Conclusion

IDegAsp is a novel co-formulation of IDeg and IAsp in a single injection that provides flat and stable basal insulin coverage and bolus mealtime insulin control, with no requirement for resuspension and reduced injection burden relative to standard basal-bolus therapy.

Clinical trials have shown that IDegAsp is associated with effective glycemic control and low rates of hypoglycemia in both Japanese and international populations.

The initiation, switching from other insulins, and titration of IDegAsp is straightforward, whether administered once or twice daily. It offers appropriate Japanese patients a simple and effective insulin regime, with the flexibility to suit individual needs.

4. Expert opinion

The molecular properties of IDeg and IAsp are such that they can be combined to yield a co-formulation product that can effectively control postprandial and fasting hyperglycemia, without increasing the risk of hypoglycemia beyond that of more conventional insulin regimens. This has been demonstrated in both international and Japanese populations with T2D [28–30,32,33,35].

Basal insulin alone becomes insufficient and controlling postprandial hyperglycemia becomes ever more important as T2D progresses, but the benefits of initiating IDegAsp are observed in insulin-naïve and insulin-experienced patients alike. The safety and efficacy of switching from other insulin regimens (biphasic, prandial, and basal) is summarized in Table 1, showing consistently lower insulin dose requirements for IDegAsp versus biphasic or prandial comparators.

One major advantage of IDegAsp is that it allows basal insulin therapy to be intensified without additional daily injections. This is important because the main reasons for clinical inertia with insulin intensification include patients’ fear of injections and the impact of burdensome regimens on quality of life. Therefore, the use of IDegAsp may provide an attractive alternative to full basal-bolus and premix insulin regimens for patients (with T1D or T2D) requiring a mealtime insulin dose. This might facilitate more timely insulin intensification, helping patients to achieve and maintain glycemic control and avoid diabetes-related complications later in life. To help achieve this, detailed practical guidance on initiating and titrating IDegAsp is required.

Further studies are required to evaluate the use of IDegAsp in routine clinical practice, and investigate whether it can help tackle clinical inertia. For example, observational studies comparing IDegAsp with other insulin regimens (premix, basal, basal-bolus) in terms of HbA_1c reduction, rates of hypoglycemia and patient-reported outcome questionnaires, which assess quality of life and adherence, together with physician surveys that measure provider experience, are required to evaluate the impact of this co-formulation on routine clinical practice. These real-world studies will help identify which patients benefit most from IDegAsp. Furthermore, the above-mentioned studies should also build on findings from special patient populations, such as elderly patients and patients with renal impairment [19]. For example, studies should investigate the effectiveness of IDegAsp in meeting glycemic targets recommended in the latest Japanese society guidelines for elderly patients treated with drugs potentially associated with severe hypoglycemia, such as insulin [41]. The evidence so far suggests that this novel co-formulation of IDeg and IAsp will be an effective diabetes therapy to meet these treatment challenges.

Article highlights

• Insulin degludec/insulin aspart (IDegAsp) is the first soluble co-formulation of a basal insulin with an ultra-long duration of action (IDeg) and a rapid-acting bolus insulin (IAsp) in a single injection.

• Glucose infusion rate profiles show discrete prandial and basal effects of IDegAsp in Caucasian and Japanese patients, with a rapid onset of IAsp action, followed by a separate, flat and stable basal effect of IDeg.

• In Phase 3 trials, IDegAsp resulted in improved glycemic control, low rates of hypoglycemia and a low end-of-trial insulin dose in international and Japanese populations.

• It is straightforward to initiate and titrate IDegAsp, whether administered once or twice daily and whether switching from basal or premixed insulin.

• Further studies are required to evaluate the use of IDegAsp in routine clinical practice, and investigate whether it can help tackle clinical inertia.

This box summarizes key points contained in the article.

Declaration of interest

T Hirose has been on advisory panels for Sanofi, Eli Lilly and Company and Novo Nordisk. He has received research support from Sanofi, Eli Lilly, Novo Nordisk, Takeda, Daiichi Sankyo, Mitsubishi Tanabe, Dainippon Sumitomo, Kissei, Boehringer Ingelheim, Astellas, Ono Pharmaceutical Ltd, AstraZeneca, Taisho Toyama, Novartis and Merck Sharp and Dohme (MSD). He has been on the speakers’ bureau for Sanofi, Eli Lilly, Novo Nordisk, Takeda, Mitsubishi Tanabe, MSD, Dainippon Sumitomo, Novartis, Kissei, Boehringer Ingelheim, Ono Pharmaceutical Co. Ltd and AstraZeneca. T Awata is on the advisory boards of, received speaker honoraria from, and received research grants from Novo Nordisk, MSD, Mitsubishi Tanabe Pharma, Astellas Pharma, Sanwa Kagaku Kenkyusho, Ono Pharmaceutical Co. Ltd, Eli Lilly, Sumitomo Dainippon Pharma and Novartis. Y Yamamoto is an employee of Novo Nordisk Pharma Ltd. while MP Hemmingsen is an employee and stockholder of Novo Nordisk Pharma Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript and funded by Novo Nordisk. One reviewer served as a consultant and speaker for Novo Nordisk. However, this did not involve the product being discussed here.

Acknowledgments

Medical writing and submission support were provided by Julie Sawyers, Victoria Atess, Richard McDonald and Beverly La Ferla of Watermeadow Medical, an Ashfield Company, part of UDG Healthcare plc.

Additional information

Funding

This study was supported by Novo Nordisk. Medical writing and submission support was funded by Novo Nordisk