Idegasp Provides Simple Intensification Without the Addition of Another Insulin Injection and Simple Delivery System

CASE REPORT Diabetes Management

IDegAsp provides simple intensification without the addition of another insulin injection and simple delivery system

Shizuka Kaneko*, Youhei Ueda, Yumiko Tahara

ABSTRACT Insulin degludec (IDeg) is an ultra-long duration novel basal insulin analogue, with flat and stable glucose-lowering effect. Translating into lower rates of hypoglycemia, especially nocturnal episodes, compared to conventional basal insulin in patients with T2DM, and have the potential for flexible dosing times to accommodate varying lifestyles. A co-formulation of IDeg and the rapid-acting analogue insulin aspart (IAsp) results in the soluble co-formulation insulin degludec/insulin aspart (IDegAsp). This provides both mealtime coverage and full 24-h basal coverage in a single injection. We confirmed the effectiveness of the intensification of therapy by substitution of basal insulin or conventional premix insulin with newly premix insulin IDegAsp in uncontrolled patients by continuous glucose monitoring (CGM). Novel soluble co-formulation insulin degludec/insulin aspart, IDegAsp, provides a simple helpful intensification for poorly controlled T2DM patients on basal insulin and every T2DM patient administrated conventional premix. Using IDegAsp is a patient-friendly intensified insulin therapy from the point of view that it is simple delivery system without need for reconstitution before injection and with no need for additional insulin injections.

Introduction when therapy intensification using meal-time bolus insulin should be started. (a) when fasting An ultra-long duration novel basal insulin glucose levels are at target but HbA1c remain analogue degludec (IDeg) has a 25 h half- above goal after 3–6 months of basal insulin life with flat and stable glucose-lowering titration; (b) when significant postprandial effect at steady state [1]. It has four-times less glucose excursions (more than 180 mg/dL]) pharmacodynamic variability than insulin occur; (c) when nocturnal or postprandial glargine (IGlar) [2] Translating into lower rates hypoglycemia occurs by increasing basal insulin of hypoglycemia, especially nocturnal episodes, dosage [7]. compared to IGlar in patients with T2DM [3], and has the potential for flexible dosing times to IDegAsp has been newly launched and is already accommodate varying lifestyles [4]. Moreover in widespread use in several countries in Asia. We it is possible to change dosing times of IDeg to will introduce CGM results which demonstrate accommodate varying lifestyles [5]. the effectiveness of the intensification of therapy by changing basal insulin or conventional A co-formulation of IDeg and the rapid-acting premix insulin to IDegAsp. Moreover, we will analogue insulin aspart (IAsp) results in the show CGM results of blood glucose fluctuation soluble co-formulation insulin degludec/insulin in patients undergoing dialysis who were aspart (IDegAsp: 70% v/v IDeg as basal insulin administered IDegAsp. and 30% v/v IAsp as prandial insulin). This provides both mealtime coverage and full 24-h Results basal coverage in a single injection [6]. The most recent ADA/EASD position statement describes Informed consents were obtained, and prior

Takatsuki Red Cross Hospital, Takatsuki, Japan *Author for correspondence: [email protected]

Diabetes Manag (2017) 7(1), 177–185 ISSN 1758-1907 177 CASE REPORT Kaneko, Ueda, Tahara

KEYWORDS insulin therapy was switched to IDegAsp therapy. insulin component can improve the postprandial glucose level whilst maintaining the fasting ■■IDegAsp Case 1: A sixty-nine year-old female patient with glucose target (FIGURE.1 and 2). ■■conventional premix T2DM (FIGURE 1). Case 3: A seventy-eight year-old male patient ■■CGM Case 2: A seventy-three year-old female patient with T2DM was administered simplified therapy with T2DM, who is insulin antibody positive ■■type 2 diabetes employing co-formulated IDegAsp. Although (FIGURE 2). ■■insulin therapy IDeg plus insulin aspart therapy was simplified ■■simple delivery system By switching from IDeg to IDegAsp, the bolus changing to IDegAsp, his CGM result shows

Figure 1: Case1: A sixty-nine year-old female patient with T2DM.

Figure 2: Case 2: A seventy-three year-old female patient with T2DM who is insulin antibody positive.

178 Diabetes Manag (2017) 7(1) IDegAsp provides simple intensification Case Report blood glucose fluctuation was completely same intake, resulting in hyperglycemia before dinner. as before and after changing (FIGURE 3). Hyperglycemia before dinner causes hyperglycemia after dinner, although escalation due to dinner Although both patients were administered intake is small. However, once the optimal timing with basal insulin for type 2 diabetes, the 2-h of IDegAsp injection has been found, overall blood postprandial glucose level remained over 200- glucose control would be expected to improve. His 250 mg/dl even when achieving the fasting CGM result suggests that it is needed to decrease glucose target. of the dosage of IDegAsp when changed from Case 4: CGM result shows that escalation of blood glargine (FIGURE 4). glucose levels largely increases due to lunch meal The insulin therapy can be intensified without

Figure 3: Case 3: A 78 year-old male patient with T2DM.

Figure 4: Case 4: A ninety year-old male patient with T2DM.

179 CASE REPORT Kaneko, Ueda, Tahara

the addition of another insulin injection before (FIGURE 7). His CGM result of IDegAsp plus meals. Therefore, this intensifies insulin therapy dulaglutide therapy shows stable blood glucose with the added benefit of a simplified drug control (FIGURE 8). delivery. Case 8: Steroid induced hyperglycemia caused Case 5: Premix insulin such as IDegAsp fulfils escalation of blood glucose levels after lunch. the long-held expectation that for patients with Therefore, injection of IDegAsp before lunch T2DM, premix insulin would be developed to can be helpful and effective for a patient who is change the basal component of intermediate suffering from steroid induced hyperglycemia. insulin to longer acting basal insulin in order A seventy-three year old female patient with to achieve better blood glucose control and T2DM and Rheumatoid Arthritis was suffering decrease hypoglycemia. Higher percentages from steroid induced hyperglycemia and swan- of patients using IDegAsp are achieving their neck deformity in her fingers. Change from personal Hb1Ac targets with a lower risk for NPH plus regular insulin therapy to IDegAsp hypoglycemia compared with those patients simplified insulin injection and helped her using conventional premix. The total daily dose (FIGURE 9). of insulin is expected to decrease when changed from conventional premix (FIGURE 5). There Discussion is also no need for reconstitution. Ralph deFronzo reported that deterioration of Cases 6 and 7: IDeg is a useful option for patients β cell function was significant and glucagon with renal impairment, including patients secretion in the fasting state from β-cells was undergoing dialysis. I therefore conclude that upregulated in patients with type 2 diabetes, IDegAsp also can provide a stable control of especially in those patients with a blood glucose blood glucose in T2D patients on dialysis level of over 140 mg/dL [8]. Müller et al. [9] and (FIGURES 6 and 7). Mitrakou et al. [10] demonstrated that insulin Case 7: Case is of a seventy-four year-old male secretion in healthy subjects occurs rapidly by patient with T2DM and liver cirrhosis Child A. glucose loading, which is the first phase of insulin Regular insulin therapy was switched to IDegAsp secretion and results in suppression of glucagon therapy. Next, GLP1RAg therapy was added through zinc binding to SUR on α-cells [11].

Figure 5: Case 5: A sixty-nine year-old female patient with T2DM.

180 Diabetes Manag (2017) 7(1) IDegAsp provides simple intensification Case Report

Figure 6: Case 6: Hemodialysis Case: A sixty-one year-old male patient with T2DM. IDegtherapy was switched to IDegAsp therapy.

Figure 7: Case 7-a: Hemodialysis case. A seventy-four year-old male patient with T2DM and liver cirrhosis child A.

Glucagon is reported to contribute approximately causes the increase in fasting and postprandial half of the increases in blood glucose levels blood glucose levels. IDeg, ultra-long acting after meals. Collectively, gluconeogenesis and basal insulin, provides uniform insulin coverage glycogenolysis through upregulation of glucagon throughout the day and night and is prescribed enhance hepatic glucose production, which mainly to control blood glucose by suppressing

181 CASE REPORT Kaneko, Ueda, Tahara

Figure 8: Case 7-b: CGM result of IDegAsp plus dulaglutide therapy in the case 7.

Figure 9: Case 8: A seventy-three year old female patient with T2DM and rheumatoid arthritis. Average; Average of blood glucose level per day (mg/dl) SD; standard deviation of blood glucose level per day (mg/dl)

hepatic glucose production in between meals blood glucose levels improves endogenous insulin and during sleep [12-14]. secretion and incretin action, which in turn will act on alpha cells to suppress enhanced glucagon This means that exogenous basal insulin and will result in the decrease in hepatic glucose treatment with the aim of lowering the fasting production and improvement in postprandial

182 Diabetes Manag (2017) 7(1) IDegAsp provides simple intensification Case Report glucose levels, effectively, through physiological long-acting insulin analogue, injection timing processes. and dosing can be changed. It was reported that basal insulin treatment to The therapeutic options of once daily injections, achieve the fasting blood glucose target of 100 such as: A) Basal insulin, B) The more intensified mg/dl, enhances hepatic glucose uptake via option, IDegAsp and C) Basal insulin plus the improvement of endogenous insulin secretion OHAs (DPP4 inhibitor, SGLT2 inhibitor, alpha- and decreases postprandial glucose levels [15]. glucosidase inhibitor, glinide, or biguanide), all enable us to move toward greater intensification In addition, it was reported that there was of therapy and patient-centered care for those a correlation between fasting blood glucose with T2DM [20]. levels and total endogenous insulin secretion in Japanese subjects. Therefore total insulin A more complex treatment regimen with several secretion was lower at fasting blood glucose injections of rapid-acting insulin at meal times levels over 110 mg/dL [16]. Taken together, is necessary when the patient is not tolerant to pancreatic beta-cells may no longer maintain a GLP-1 receptor agonist or when the glucose total insulin secretion at adequate fasting blood target is not achieved, even with the combination glucose levels, and exogenous basal insulin therapy of basal insulin and a GLP-1 receptor treatment targeting fasting blood glucose levels agonist. lower than 100 mg/dL may improve endogenous Treatment can be intensified by prescribing 2 postprandial insulin secretion. It is also reported or 3 injections per day before meals with basal that administration of basal insulin over 8 weeks insulin treatment, or, alternatively, utilizing results in improvements in first- and second- IDegAsp therapy to avoid increasing the number phase insulin secretion [17]. of injections. When appropriate and timely introduction The intensification of therapy by of insulin is needed before the loss of the substitution of IDegAsp for conventional endogenous insulin secreting ability in patients premix insulin with type 2 diabetes, treatment with long acting basal insulin should be considered as an Conventional premix insulin contains alternative to in multiple insulin injections. intermediate insulin as the basal insulin component, and therefore has a peak effect However, the introduction of long acting which might carry the risk of hypoglycemia basal insulin treatment might not improve the before dinner and during the night. In addition, postprandial glucose level, even when achieving since its basal insulin component does not cover the fasting blood glucose target, in this instance, IDegAsp could be useful, because it provides 24 h, it is difficult to achieve the fasting blood stable fasting blood glucose level and decreases glucose target of 100 mg/dl. Moreover, the postprandial blood glucose once or twice postprandial blood levels are also not at goal depending on the number of insulin injections because endogenous insulin secretion can’t be administrated. improved to required levels. Therefore changing from premixed insulin to IDeg/Asp might solve Intensification employing Novel insulin the problems in those patients with T2DM. analogue combinations Simply switching to a novel co-formulated short When intensification is needed to decrease post plus long acting insulin analogue combination prandial glucose levels after stabilization of like IDegAsp can intensify insulin therapy fasting blood glucose levels, a short acting insulin whilst decreasing the risk of hypoglycemia and analogue before meals is needed. It was reported overcoming the limitations of premixed insulin. that glargine plus one insulin injection before The total daily insulin dosage needed could be a main meal improved HbA1c [18]. Instead reduced for IDegAsp, compared to employing of administering another insulin injection, premix 30, whilst at the same time achieving the switching from long acting basal analogue same HbA1c levels and better FPG levels with insulin to IDegAsp, it makes it possible to easily a lower incidence of nocturnal hypoglycemic intensify insulin therapy with only one daily events [21,22]. In addition, with IDegAsp injection instead of 2 daily injections [19]. there is also no need for reconstitution. On Since the basal insulin component of the co- the other hand, it is necessary when employing formulated, IDegAsp combination, is an ultra- conventional premixed insulin’s.

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Insulin use in T2DM patients with renal This means that a different dosage is needed on impairment the day of dialysis with conventional insulin. However, with IDeg or IDegAsp there is, in Finally, IDeg is a useful option for patients many cases, no need to change dosage with only with renal impairment [23], including patients minimal changes in dosage necessary in some undergoing dialysis. cases. In Japan, dialysis is performed in one out of 400 Thirdly, another important mechanism is a people in the Japanese population. It has taken a change in the pH of glargine in the body fluid tremendous effort to treat patients with insulin before and after dialysis. Glargine is acidic therapy who are undergoing dialysis. and soluble at pH 4 in the vial. Glargine is However, after the approval of IDeg, we can precipitated at the isoelectric point, pH6, in the provide a safer and more efficient therapy with electrically neutral hypodermis, and is slowly or without using a combination of GLP1RA plus dissolved and absorbed into the bloodstream IDeg or GLP1RA plus IDegAsp. First, IDeg is [24]. In patients undergoing dialysis, the pH of conjugated with fatty acid, and binds to albumin the body fluid is around 7.0 before dialysis and in the blood. Hormones, for example, cortisol, around 7.4 after dialysis. thyroid hormones and testosterone employ This causes a difference in the solubility and carrier proteins and therefore fluctuations in absorption of glargine. the concentrations of hormones remain stable and minimal. In the same way, IDeg employs In fact, the glycemic control of some patients on albumin as a carrier protein with similar minimal dialysis who can switch from basal-bolus therapy fluctuations. As IDegAsp consists of 70% v/v to once daily IDeg doesn’t worsen. IDeg as basal insulin, it might act, therefore, in almost the same way. Conclusion Secondly, NPH insulin and insulin glargine are Novel soluble co-formulation insulin degludec/ precipitated in crystalline form after subcutaneous insulin aspart, IDegAsp, provides a simple helpful injection, while IDeg or IDegAsp are not. So, intensification for poorly controlled T2DM neither of the interstitial fluid volumes before or patients on basal insulin, those in whom it is after dialysis affects the dissolution of IDeg or difficult to escalate/intensify insulin therapy, and IDegAsp. every T2DM patient administrated conventional Since body fluid is abundant before dialysis, premix. Furthermore, simple intensification precipitated insulin enters the blood stream without the addition of another insulin injection more quickly. On the other hand, since body and a simple delivery system, i.e., no need for fluid is reduced after dialysis and subcutaneous reconstitution before injection, is helpful from a interstitial fluid is minimal, precipitated insulin patient’s perspective. Taken together, these result is more stable than usual. in a patient-friendly intensified insulin therapy.

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