Fast-acting insulin aspart (Fiasp®) improves glycemic outcomes when used with MiniMedTM 670G hybrid closed-loop system in simulated trials compared to NovoLog®
Introduction
In the past two decades, academic and industry groups have been investigating subcutaneous sensor-augmented insulin pumps to deliver insulin automatically for people with diabetes mellitus. The concept, known as closed-loop, is based on classic control theory that uses feedback control to deliver insulin automatically to regulate measured sensor glucose (SG) values. The technology or algorithms involved in these investigations are also known as artificial pancreas systems.
The MiniMedTM 670G system (Medtronic, Northridge, CA, USA) was the first commercially available closed-loop (CL) system. It is currently used by over 250,000 patients in the United States and Europe combined with clinically significant improvement in glycemic control when compared to non-automatic insulin delivery therapy systems [1].
The effectiveness of regulating glucose by subcutaneous insulin administration is limited by the rate of the onset and half-life of current rapid-acting insulin analogs [2,3], which are slower than endogenously secreted insulin action and can limit the responsiveness of CL system insulin delivery to sudden increases or decreases in glucose levels limiting the effectiveness and safety of CL systems. Furthermore, the insulin delivery into the blood from the subcutaneous depot cannot be turned on and off rapidly in response to changes in glucose, like the pancreas.
The commercially available faster insulin aspart analog Fiasp® (Novo Nordisk A/S, Bagsværd, Denmark) shortens both the onset and half-life of insulin [4]. This was accomplished by a change in the insulin aspart (NovoLog®) formulation that involves the addition of two excipients: niacinamide, which facilitates a more rapid breakdown of insulin hexamers after subcutaneous administration and increases local blood flow thereby accelerating insulin absorption [5], and L-arginine hydrochloride intended to support the monomeric stabilization of the Fiasp® formulation. Therefore, Fiasp® has the potential to further improve glycemic outcomes regulated via insulin delivery with CL systems.
Using many clinical trials to evaluate and optimize drug therapy are time consuming and expensive. On the other hand, mathematical models offer powerful and affordable alternatives that can reduce the number of clinical trials by predicting and narrowing the number of hypotheses and even predict the optimal therapies.
The “minimal model” (Bergman et al. [6]) that describes glucose dynamics following intravenous glucose administration (IVGTT) was a major breakthrough in diabetes mathematical modeling [7]. Based on this modeling effort the ‘UVa/Paduva simulator’ [8] was developed which was approved by the US Food and Drug Administration (FDA) as a replacement for certain animal studies. Another important work in insulin-meal-glucose dynamics modeling was presented by Hovorka et al. [9]. A more detailed and constructive review of minimal models of glucose dynamics in diabetes can be referred to in Cobelli et al. [10].
The utilization of glucose kinetics mathematical models for designing novel insulin therapies was introduced by several research groups in the last decade [11,12]. We developed a glucose kinetic mathematical model to be able to fit to noninvasive patient data that includes insulin deliveries, glucose sensor measurements, and some user self-reported carbohydrate intakes. An early version of our simulation environment for modeling and predicting insulin therapy outcomes for people with type 1 diabetes (T1D) was reported in Grosman et al [13]. An enhanced simulator was created with larger virtual-patient population, longer simulation time and among others includes a patient specific meal bolus timing mismatches and missed meal boluses scenarios. The PK/PD assumptions used in our virtual patients population were compared to published data and are well in the range of the experimental data and the meal rates of absorption were compared to literature and found to be well in the range of the experimental data.
The mathematical model presented in this work was validated in as reported in Grosman et al [13] where the model was used to successfully predict the outcomes of two recent clinical trials of the Medtronic threshold suspend [14] algorithm used in the MiniMedTM 530G, Veo, and 630G systems and the MiniMedTM 670G system [15]. A simulation environment based on the virtual-patients model was also used to design and tune the new Medtronic MiniMedTM 780G insulin pump system's Smart Guard Auto-Mode algorithm. This procedure allowed Medtronic Diabetes to proceed from in-silico design directly into clinical trial with humans with outcomes that matched the simulated predicted outcomes [16,17]. The ability to design and tune the 780G Smart Guard Auto Mode and at the same time predict the clinical outcomes is a testimony to the validity of the mathematical model presented in this work.
As was demonstrated in other simulation studies with fast acting inhaled insulins, [18,19] we conducted simulation studies using the MiniMedTM 670G system with standard NovoLog® (EU: NovoRapid, US: NovoLog) versus Fiasp® to determine whether Fiasp® can improve the percentage of time spent in the euglycemic range (70 – 180 mg/dL), without increasing the risk of hypoglycemia.
Section snippets
Clinical trial data
Novo Nordisk A/S data from the following two single-center, two-period, crossover clinical trials NN1218-3890 with 46 participants and NN1218-4349 with 55 participants was used to estimate the pharmacokinetics (PK) and pharmacodynamics (PD) of NovoLog® and Fiasp®. Each study participant received both NovoLog® and Fiasp® in two different visits with a washout period of 3 to 12 days between visits. The visit protocol included a 27-hour-long study consisting of 11 h of a run-in period, 2 h of a
Analysis of overall simulated glycemic distribution
Fig. 4 depicts averaged simulated glycemic distributions for 7607 virtual patients in which NovoLog® was compared to Fiasp®. Glycemic distribution is assessed as percentage of time spent in different glycemic regions. On average, the simulations indicate that, by switching from NovoLog® to Fiasp®, the overall glycemic distribution resulted in a reduced percentage of time in hyperglycemia (>180 mg/dL), and greater percentage of time in the euglycemic range (70-180 mg/dL) without an increase to
Discussion
Various professional societies including the American Diabetes Association recommend that the target for HbA1C is <7% in most patients [22]. Clinicians regard a 0.3-0.4% change in HbA1C in either direction as being clinically relevant. While the targets for the various times in ranges have been defined, e.g., 70-180 mg/dL (>70%), <70 mg/dL(<4%) and <54 mg/d (<1%) [23] there is no consensus of what constitutes a clinically significant change particularly in the hypoglycemia range of <70 mg/dL
Declaration of Competing Interest
Grosman, Benyamin, Wu Di, Parikh Neha, Roy Anirban, Gayane Voskanyan, Kurts Natalie, Cohen Ohad, and Vigersky Robert are Medtronic plc employees and share holders
Sturis Jeppe and Ekelund Magnus are Novo Nordisk A/S employees and share holders
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