A New-Generation Ultra-Long-Acting Basal Insulin With a Bolus Boost Compared With Insulin Glargine in Insulin-Naïve People With Type 2 Diabetes: A randomized, controlled trial

TIM HEISE CEES J. TACK ROBERT CUDDIHY JAIME DAVIDSON DIDIER GOUET ANDREAS LIEBL ENRIQUE ROMERO HENRIETTE MERSEBACH PATRIK DYKIEL MSC ROLF JORDE OBJECTIVE-Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the novel basal analog insulin degludec (IDeg: 70%) and insulin aspart (IAsp: 30%). We compared the safety and efficacy of IDegAsp, an alternative formulation (AF) (55% IDeg and 45% IAsp), and insulin glargine (IGlar) in insulin-nave subjects with type 2 diabetes inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS-In this 16-week, open-label trial, subjects (mean age 59.1 years, A1C 8.5%, BMI 30.3 kg/m2) were randomized to once-daily IDegAsp (n = 59), AF (n = 59), or IGlar (n = 60), all in combination with metformin. Insulin was administered before the evening meal and dose-titrated to a fasting plasma glucose (FPG) target of 4.0-6.0 mmol/L. - RESULTSAfter 16 weeks, mean A1C decreased in all groups to comparable levels (IDegAsp: 7.0%; AF: 7.2%; IGlar: 7.1%). A similar proportion of subjects achieved A1C ,7.0% without confirmed hypoglycemia in the last 4 weeks of treatment (IDegAsp: 51%; AF: 47%; IGlar: 50%). Mean 2-h postdinner plasma glucose increase was lower for IDegAsp (0.13 mmol/L) and AF (0.24 mmol/L) than IGlar (1.63 mmol/L), whereas mean FPG was similar (IDegAsp: 6.8 mmol/L; AF: 7.4 mmol/L; IGlar: 7.0 mmol/L). Hypoglycemia rates were lower for IDegAsp and IGlar than AF (1.2, 0.7, and 2.4 events/patient year). Nocturnal hypoglycemic events occurred rarely for IDegAsp (1 event) and IGlar (3 events) compared with AF (27 events). CONCLUSIONSIn this proof-of-concept trial, once-daily IDegAsp was safe, well tolerated, and provided comparable overall glycemic control to IGlar at similar low rates of hypoglycemia, but better postdinner plasma glucose control. A sulin analogs have advantages over lthough currently available basal in NPH insulin, they fail to completely mimic the physiological basal insulin secretion profile; at higher doses in particular, their profile is not completely flat, but shows a gentle rise and fall (1). Furthermore, lower doses do not achieve 24-h insulin coverage in all individuals (2), and there remains some within-subject variability in the metabolic effect impeding optimal insulin titration. These limitations, together with a lack in postprandial insulin coverage, may partly explain why a large proportion of patients with type 2 diabetes fail to reach and maintain recommended A1C targets (35) considered to minimize the risk for microvascular complications (68). To provide more optimal basal insulin coverage, insulin degludec (IDeg), a new-generation ultra-long-acting basal insulin, was developed. Primarily as a result of the formation of soluble multihexamers at the injection site, IDeg has a smooth and stable pharmacokinetic profile at steady state (9) that gives rise to a considerably longer action profile than current basal insulin formulations (10) as well as lower within-subject variability (11). IDeg can be coformulated with insulin aspart (IAsp) (12) resulting, for the first time, in a soluble preparation comprising two different insulin analogs (IDegAsp: 70% v/v IDeg as basal insulin and 30% v/v IAsp as prandial insulin). By providing both basal and rapid-acting insulin analogs in one injection, IDegAsp could be an attractive alternative to the common strategy of initiating insulin therapy with basal insulin only on top of oral antidiabetic drugs (OADs). Indeed, for many patients, simultaneously targeting fasting and postmeal plasma glucose could be a more suitable approach to achieving and sustaining optimal glycemic control (13). In this exploratory, clinical proof-ofconcept trial, we compared the safety and efficacy of IDegAsp with insulin glargine (IGlar), both given once-daily in combination with metformin in insulin-nave subjects with type 2 diabetes inadequately controlled on OAD therapy. To establish the optimal ratio of IDeg to IAsp, an alternative formulation of IDegAsp (AF) containing a higher percentage of IAsp (45%) was also evaluated. RESEARCH DESIGN AND METHODSTwenty-two sites in five European countries (France, Germany, Norway, Romania, and Spain) participated in this phase 2, open-label, randomized, controlled 16-week trial. The trial protocol was approved by local institutional review boards, and all subjects gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki (14) and Good Clinical Practice guidelines (15). Trial population Adults with type 2 diabetes were enrolled if they were 1875 years of age, had an A1C of 711%, and had a BMI of 2537 kg/m2. Subjects had to be insulin-nave (no previous insulin treatment or insulin treatment for #14 days in the 3 months prior to trial), and had to be treated with up to two OADs in the 2 months prior to trial at stable maximum doses or at least half maximum allowed doses. Subjects were excluded if they had been treated with thiazolidinediones in the 3 months preceding the trial. Other exclusion criteria included cardiac disease (heart failure: New York Heart Association class III or IV, unstable angina pectoris, or a myocardial infarction) within 12 months of the trial, severe hypertension (systolic blood pressure $180 mmHg or sitting diastolic blood pressure $100 mmHg), recurrent severe hypoglycemia or hypoglycemia unawareness, use of drugs likely to affect glycemia, impaired hepatic function (alanine aminotransferase .2.5-fold the upper local reference limit), pregnancy, and breast-feeding. Treatments Prior to randomization, eligible subjects discontinued their pretrial OAD treatment and underwent a 2-week forced metformin titration period (dose increased up to 2,000 mg/day: 1,000 mg each at breakfast and the evening meal) followed by a 1-week metformin maintenance period. Subjects taking metformin at enrollment could undergo a modified titration period or advance directly to the metformin maintenance period. Metformin could be decreased to a minimum of 1,500 mg/day in the case of unacceptable hypoglycemia or other adverse events. Subjects were eligible for randomization provided the maximum daily metformin dose (2,000 mg) or maximum tolerated dose (1,500 mg) remained unchanged in the maintenance period and the median prebreakfast self-measured plasma glucose (SMPG) value (measured on the 3 days prior to randomization) was $7.5 mmol/L (135 mg/dL). Randomization was carried out using a telephone- or web-based randomization system, with subjects stratified according to pretrial OAD treatment (Table 1). Eligible subjects were randomized (1:1:1) to receive once-daily subcutaneous injections of either IDegAsp (70% IDeg and 30% IAsp; Novo Nordisk A/S, Bagsvrd, Denmark; 100 U/mL), AF (55% IDeg and 45% IAsp; Novo Nordisk A/S, Bagsvrd, Denmark; 100 U/mL) or IGlar (Lantus; sanofi-aventis, Paris, France; 100 U/mL) for 16 weeks, all in combination with metformin. The insul (...truncated)