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Home , Biguanide, Insulin (medication), Insulin aspart, Insulin degludec, Insulin glargine, Pioglitazone

2084 Care Volume 37, August 2014

Gregory R. Fulcher,1 Jens Sandahl Christiansen,2 Comparison of Ganapathi Bantwal,3 Miroslawa Polaszewska- Muszynska,4 Henriette Mersebach,5 Degludec/ Thomas H. Andersen,5 and Leo K. Niskanen,6 on behalf of the BOOST: Intensify Premix I and Biphasic Insulin Aspart 30 Investigators in Uncontrolled, Insulin-Treated : A Phase 3a, Randomized, Treat-to-Target Trial Diabetes Care 2014;37:2084–2090 | DOI: 10.2337/dc13-2908 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL

OBJECTIVE /insulin aspart (IDegAsp) is the first combination of a basal insulin with an ultralong duration of action, and a rapid-acting insulin in a single injection. This trial compared IDegAsp with biphasic insulin aspart 30 (BIAsp 30) in adults with type 2 diabetes inadequately controlled with once- or twice-daily (OD or BID) pre- or self-mixed insulin with or without oral antidiabetic drugs.

RESEARCH DESIGN AND METHODS In this 26-week, randomized, open-label, multinational, treat-to-target trial, par- ticipants (mean age 58.7 years, duration of diabetes 13 years, BMI 29.3 kg/m2,and 1University of Sydney, Royal North Shore Hospi- HbA 8.4% [68 mmol/mol]) were exposed (1:1) to BID injections of IDegAsp (n = tal, Australia 1c 2Aarhus University Hospital, Aarhus, Denmark 224) or BIAsp 30 (n = 222), administered with breakfast and the main evening meal 3St. Johns Medical College Hospital, Bangalore, and dose titrated to a self-measured premeal plasma (PG) target of 4.0– India 5.0 mmol/L. 4Bydgoszcz Diabetes and Endocrinology Center, Bydgoszcz, Poland 5 RESULTS A/S, Søborg, Denmark 6School of Medicine, University of Eastern Fin- After 26 weeks, mean HbA1c was 7.1% (54 mmol/mol) for both groups, with land, Helsingfors, Finland fi IDegAsp achieving the prespeci ed noninferiority margin for mean change in Corresponding author: Gregory R. Fulcher, greg. HbA1c (estimated treatment difference [ETD] –0.03% points [95% CI –0.18 to [email protected]. 0.13]). Treatment with IDegAsp was superior in lowering fasting PG (ETD –1.14 Received 16 December 2013 and accepted 20 mmol/L [95% CI –1.53 to –0.76], P < 0.001) and had a significantly lower final mean March 2014. daily insulin dose (estimated rate ratio 0.89 [95% CI 0.83–0.96], P = 0.002). Fewer reg. no. NCT01009580, clinicaltrials confirmed, nocturnal confirmed, and severe episodes were reported .gov. for IDegAsp compared with BIAsp 30. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ CONCLUSIONS suppl/doi:10.2337/dc13-2908/-/DC1. IDegAsp BID effectively improves HbA and fasting PG levels with fewer hypo- © 2014 by the American Diabetes Association. 1c Readers may use this article as long as the work glycemia episodes versus BIAsp 30 in patients with uncontrolled type 2 diabetes is properly cited, the use is educational and not previously treated with once- or twice-daily pre- or self-mixed insulin. for profit, and the work is not altered. care.diabetesjournals.org Fulcher and Associates 2085

Insulin is the most effective therapy for in the subcutaneous tissue that slowly RESEARCH DESIGN AND METHODS achieving glycemic control in patients dissociate to provide continuous IDeg Trial Design with type 2 diabetes (1). Owing to the absorption to meet basal needs. At the A total of 50 sites in 10 countries (Aus- progressive nature of type 2 diabetes, same time, IAsp hexamers immediately tralia, Denmark, Finland, India, Malay- many patients will become candidates dissociate into monomers that are rap- sia, Poland, Sweden, Taiwan, Thailand, for prescription of insulindfrequently idly absorbed into the circulation, pro- and Turkey) participated in this multina- basal insulin initially on a variable back- viding mealtime coverage (13,14). tional 26-week, phase 3a, open-label, ground of antidiabetic therapy. How- Pharmacodynamic studies have demon- randomized, treat-to-target trial. ever, as type 2 diabetes progresses, strated that the glucose-lowering effect The protocol, protocol amendments, further treatment intensification in the of IDegAsp is characterized by a distinct consent form, and subject information form of prandial insulin is commonly peak action (from IAsp) and a separate sheet were reviewed and approved by required to achieve HbA1c targets and basal action (from IDeg). This is a closer health authorities according to local reg- potentially to avoid the long-term approximation of physiological ac- ulations and by the local independent consequences of (2). tion than seen with current biphasic ethics committees prior to trial initia- Currently, this approach is achieved formulations. The long-acting basal tion. This trial was performed in accor- through the addition of one or more component of IDegAsp allows for a dance with the Declaration of Helsinki separate prandial insulin injections to pharmacodynamic profile that is flat and Good Clinical Practice (19). All study an existing basal insulin regimen or and stable throughout the day, mimick- participants gave written consent prior by switching to premixed insulin ing that of IDeg alone (14). The IDeg to any trial-related activities, and the in- containing a fixed ratio of rapid- and component in IDegAsp has been vestigator retained the consent forms. intermediate-acting insulin (1). However, demonstrated to have a predictable several barriers remain to insulin intensi- glucose-loweringeffectanduptofour Trial Population fication. While separate basal and times lower day-to-day variability com- Adults with a clinical diagnosis of type 2 injections offer the most precise and pared with at steady- diabetes for $6 months were enrolled if adaptable mealtime glycemic control state conditions (15). Clinical trials they had an HbA1c of 7–10% (53–86 (1), they can be perceived as complex have demonstrated a lower risk of mmol/mol), had a BMI of #40 kg/m2, (1,3–5). In some patients, this may result IDeg causing hypoglycemia compared and were $18 years of age. Patients in an increased burden of treatments and with insulin glargine (16) and the possi- were on premixed human or analog decreased adherence to injections (6). bility of flexibility in the timing of injec- insulin or self-mixed insulin regimens Currently, available premix tions (17). containing 20–40% fast-/rapid-acting offer a more convenient alternative, An earlier proof-of-concept study component, administered OD or BID with fewer injections and the potential demonstrated favorable efficacy and with or without OADs (, sul- use of a single insulin pen device (7), safety profiles of IDegAsp as an add-on fonylureas, glinides, a-glucosidase but are associated with an increased to metformin in insulin-naive patients inhibitors, DPP-4 inhibitors, or pioglita- rate of postmeal hypoglycemia, including with type 2 diabetes inadequately con- zone) for $3 months prior to trial nocturnal hypoglycemia (8). The fear of trolled on oral antidiabetic drugs (OADs) initiation. hypoglycemia represents a significant (18). IDegAsp twice daily (BID) plus Patients were excluded if they had re- barrier to treatment (9,10). As a result, metformin provided overall glycemic ceived treatment in the 3 months prior patients with type 2 diabetes may con- control at lower insulin doses and signif- to trial initiation with other insulin regi- tinue to have poor glucose control and icantly lower rates of hypoglycemia mens, , or a -like an increased risk of developing diabetes- compared with the widely used pre- 1 receptor or a history related complications (1). mixed insulin, biphasic IAsp 30 (BIAsp of recurrent severe hypoglycemia (more Comprising 70% insulin degludec 30) (NovoMix 30, NovoLog Mix 70/30; than one severe hypoglycemic episode (IDeg) and 30% insulin aspart (IAsp), Novo Nordisk A/S) in combination with during the past 12 months) or hypogly- IDegAsp (Ryzodeg; Novo Nordisk A/S, metformin in insulin-naive patients with cemic unawareness. Patients were also Bagsværd, Denmark) is the first soluble type 2 diabetes with an HbA1c of 7–11% excluded if they had cardiovascular dis- combination product of a basal insulin (18). These phase 2 results, while prom- ease (: New York Heart As- with an ultralong duration of action ising, were limited by a relatively small sociation class III or IV, unstable angina and a rapid-acting insulin in a single sample size (n = 61 in the IDegAsp arm; pectoris, or a ) injection. As a soluble coformulation, n = 60 in BIAsp 30 arm) and short study within 6 months preceding trial and un- IDegAsp does not require resuspension, duration (16 weeks). controlled severe hypertension (systolic which eases administration (11) and, In this phase 3a randomized, multi- blood pressure $180 mmHg or sitting more importantly, eliminates the risk national clinical trial, the efficacy and diastolic blood pressure $100 mmHg). of incomplete mixing and therefore in- safety of IDegAsp were compared with creased hypoglycemia (12). In solution, those of BIAsp 30 in adults with type Randomization the individual components of IDegAsp 2 diabetes inadequately controlled on After randomization, eligible patients exist separately as di-hexamers (IDeg) once-daily (OD) or twice-daily (BID) discontinued their diabetic treatment and hexamers (IAsp) (13). Upon injec- premixed or self-mixed insulin regi- except for metformin, DPP-4 inhibitors, tion, the IDeg di-hexamers assemble to mens with or without concomitant and and were switched form soluble and stable multihexamers OADs. from their prior insulin to IDegAsp or 2086 IDegAsp in Insulin-Treated Type 2 Diabetes Diabetes Care Volume 37, August 2014

BIAsp 30. Patients were randomized baseline in fasting PG (FPG) and the maintenance period after stable glyce- (1:1) to BID injections of IDegAsp (100 changes in nine-point self-measured mic control and insulin dose had been units/mL Ryzodeg) or BIAsp 30 (100 PG (SMPG) profiles. Other secondary achieved. The design of this post hoc units/mL NovoMix 30, NovoLog 70/30) end points included the proportion of analysis, including the segmentation either with or without OADs (metformin patients achieving HbA1c ,7.0% (53 of the overall trial period into titration with or without dipeptidyl peptidase mmol/mol) at the end of the trial, the (0–15 weeks) and maintenance (16–26 [DPP]-4 inhibitors with or without pio- number of responders without hypogly- weeks) periods, matched that of an ear- glitazone) for 26 weeks. Randomization cemic episodes (defined as HbA1c lier preplanned meta-analysis of all IDeg was stratified based on the number of ,7.0% at end of trial with no severe or phase 3a clinical trials (16). daily insulin injections at screening to minor hypoglycemic episodes during Other adverse events were analyzed ensure equal distribution of insulin regi- thelast12weeksoftreatmentandin- using descriptive statistics. mens in the two treatment groups. As cluding only patients exposed for $12 BIAsp 30 requires resuspension prior to weeks), and the change from baseline in RESULTS injection, whereas IDegAsp does not, body weight. Patient Characteristics the trial design could not be blinded Safety variables included hypoglyce- Of the 661 patients enrolled into the and was therefore open-label. mic episodes, insulin dose, adverse study, 447 were randomized to receive events, and standard laboratory- either IDegAsp or BIAsp 30; one patient Treatment and Titration measured safety measures. Hypoglyce- Patients on premixed insulin BID were to in the BIAsp 30 group was withdrawn mia was classified as severe (requiring transfer their prebreakfast and pre– prior to receiving insulin treatment, as assistance from another person) or con- main evening meal dose 1:1 to trial in- they did not fulfill the inclusion criteria firmed (PG measurement of ,3.1 sulin. Patients on a self-mixed regimen (Fig. 1). Baseline characteristics were mmol/L [56 mg/dL] or classification were to transfer to trial insulin at doses comparable between the two treatment as severe hypoglycemia). Nocturnal corresponding to their respective self- groups including level of glycemic con- confirmed hypoglycemia included epi- mixed premeal dose. Patients previously trol, duration of diabetes, BMI, and sodes with time of onset from 0001 h receiving premixed or self-mixed insulin previous therapies (Table 1 and Supple- to 0559 h. OD were to divide their dose into two mentary Table 1). equal doses of IDegAsp or BIAsp 30 for Statistical Analyses prebreakfast and pre–main evening The primary objective of this trial was to meal administration. During the treat- demonstrate noninferiority of IDegAsp ment period, insulin dose was titrated to BIAsp 30 (noninferiority limit of based on the mean prebreakfast and 0.4%), as assessed by change in HbA pre–main evening meal plasma glucose 1c from baseline after 26 weeks. If nonin- (PG) level from the preceding 3 days. feriority was confirmed for the primary Titration of pre–main evening meal in- end point, a number of confirmatory sulin doses was based on the individual secondary end points were to be tested subject’s mean prebreakfast glucose to assess for superiority of IDegAsp over values. Treatment of prebreakfast insu- BIAsp 30. The primary efficacy end point lin doses were based on the subject’s of change from baseline in HbA after mean pre–main evening meal glucose 1c 26 weeks of treatment was analyzed values. In both cases, titration was to a using an ANOVA with treatment, antidi- self-measured PG target of 4.0–5.0 abetic therapy at screening, sex and mmol/L. region as fixed factors, and age and Insulins were administered subcu- baseline HbA as covariates. Change taneously (abdomen, deltoid, or thigh 1c from baseline in FPG, body weight, and for IDegAsp; thigh or abdominal wall PG was analyzed using the ANOVA for BIAsp 30) with breakfast and main method, similarly to the primary end evening meals. The injection region point. was kept the same for the duration The number of hypoglycemic epi- of the trial, and all insulin products sodes was analyzed using a negative bi- were administered by the FlexPen in- nomial regression model with a log-link sulin delivery device (Novo Nordisk function and the logarithm of the time A/S). Pretrial OAD dose levels re- period in which a hypoglycemic episode mained unchanged during the treat- Figure 1—Trial flow diagram. *One partici- was considered treatment emergent as ment period. pant randomized to BIAsp 30 was excluded offset. The model included treatment, from the trial before receiving insulin treat- Trial End Points antidiabetic therapy, sex, and region as ment, as the participant did not fulfill the The primary efficacy end point was fixed factors; age as a covariate; and ex- inclusion criteria. †Noncompliance with protocol-specified dosing of drug. ‡Other, change from baseline in HbA1c after 26 posure as offset. violation of inclusion/exclusion criteria, weeks of treatment. Secondary efficacy A post hoc analysis was performed to withdrawal on informed consent, lost to end points included the change from examine hypoglycemia rates during the follow-up, and other reasons. care.diabetesjournals.org Fulcher and Associates 2087

Table 1—Characteristics of randomized population units/kg for BIAsp 30 (estimated rate ra- – Characteristic IDegAsp BIAsp 30 tio [RR] 0.89 [95% CI 0.83 0.96], P = 0.002). Mean morning and evening n 224 222 doses after 26 weeks were 38 units Male/female, % 58/42 54/46 and 52 units for IDegAsp (a 42% and Age, years 58.7 (9.9) 58.8 (9.8) 58% dose split) and 44 units and 54 units Weight, kg 81.5 (18.1) 78.9 (17.6) for BIAsp 30 (45% and 55% dose split), BMI, kg/m2 29.6 (4.6) 29.0 (4.9) respectively. Duration of diabetes, years 12.8 (6.8) 13.1 (7.4) Hypoglycemic Episodes HbA1c, % 8.3 (0.8) 8.4 (0.9) Confirmed hypoglycemia (severe or PG FPG, mmol/L 8.9 (2.9) 8.6 (2.6) ,3.1 mmol/L) was reported for 66.1% Prestudy insulin regimen, n (%) Premixed or self-mixed OD 6OADs 16 (7.1) 12 (5.4) and 68.9% of patients in the IDegAsp Premixed or self-mixed BID 6OADs 203 (90.6) 206 (92.8) and BIAsp 30 groups, respectively Basal bolus 6OADs 4 (1.8) 3 (1.4) (Table 2). Superiority of IDegAsp versus Only OADs* 1 (0.4) d BIAsp 30 was demonstrated with a 32% Premixed or self-mixed three times daily d 1 (0.5) reductioninconfirmed hypoglycemic OAD (1 only) 125 (55.8) 138 (62.2) episodes: 9.7 vs. 14.0 episodes per a-Glucosidase inhibitor 2 (0.9) 3 (1.4) patient-year for IDegAsp and BIAsp 30 117 (52.2) 125 (56.3) 4 (1.8) 10 (4.5) groups, respectively (estimated RR 2 (0.9) d 0.68 [95% CI 0.52–0.89], P = 0.0049) 2 OADs 40 (17.9) 33 (14.9) (Fig. 2C). A significant 73% reduction .2 OADs 8 (3.6) 8 (3.6) in nocturnal confirmed hypoglycemia Data are mean (SD) unless otherwise indicated. *This individual was randomized in error and was observed for IDegAsp versus BIAsp was later withdrawn from the trial without being exposed to the trial drug. 30: 0.7 vs. 2.5 episodes per year, re- spectively (RR 0.27 [95% CI 0.18– 0.41], P ,0.0001) (Fig. 2D). Severe hypoglycemia was infrequent in both treatment groups (IDegAsp, 3.1%; Glycemic Control breakfast (ETD 20.98 mmol/L [95% CI BIAsp 30, 7.2%) with rates of 0.09 and After 26 weeks of treatment, the ob- 21.58 to 20.39]), and before breakfast 0.25 events per year, representing a served mean 6 SD HbA1c decreased the following day (ETD 20.85 mmol/L 50% numerical reduction for IDegAsp from 8.3 6 0.8% at baseline to 7.1 6 [95% CI 21.21 to 20.48]) were signifi- (RR 0.50 [95% CI 0.19–1.30], P=not 0.9% with IDegAsp and from 8.4 6 cantly lower with IDegAsp compared significant). 0.9% at baseline to 7.1 6 0.9% with with BIAsp 30. Similarly, the overall In a post hoc analysis of the mainte- BIAsp 30 (Fig. 2A). For the primary end mean glucose level at 26 weeks (as eval- nance period of treatment (from 16 point of mean change from baseline in uated by SMPG levels) was significantly weeks to end of trial after stable glyce- HbA1c, IDegAsp was noninferior to BIAsp lower with IDegAsp compared with mic control and insulin dose had been 30 (estimated treatment difference [ETD] BIAsp 30 (ETD 20.4 mmol/L [95% achieved), statistically significant and 20.03% points [95% CI 20.18 to 0.13]). 2 2 CI 0.75 to 0.05]) (Supplementary more pronounced reductions were The proportion of patients achieving Fig. 2). seen in all hypoglycemia categories. HbA1c targets of ,7.0% (53 mmol/mol) A numerically higher proportion of More specifically, a 39% reduction in was comparable between IDegAsp patients in the IDegAsp group compared overall confirmed hypoglycemia (RR (50.4%) and BIAsp 30 (48.6%). The with the BIAsp 30 group (37.9% vs. 0.61 [95% CI 0.45–0.83], P=0.0015), odds of achieving this target without 23.0%) reached the prebreakfast target 77% reduction in nocturnal confirmed hypoglycemic episodes during the last of ,5 mmol/L. The proportion of pa- hypoglycemia (RR 0.23 [95% CI 0.13– 12 weeks were 60% higher for IDegAsp tients achieving the same SMPG target 0.41], P , 0.0001), and an 89% reduc- (21% of patients) than for BIAsp 30 (14% predinner was comparable between the tion in severe hypoglycemic episodes of patients): odds ratio 1.60 (95% CI two insulin groups (14.7% vs. 13.1% for (RR 0.11 [95% CI 0.01–0.91], P=0.04) 0.94–2.72) (Supplementary Fig. 1). IDegAsp and BIAsp 30, respectively). were observed for IDegAsp compared Observed mean (SD) FPG decreased with BIAsp 30. from 8.9 6 2.9 mmol/L at baseline to Body Weight The observed body weight change from 5.8 6 1.9 mmol/L for IDegAsp and Adverse Events baseline to week 26 with IDegAsp (in- from 8.6 6 2.6 mmol/L to 6.8 6 2.4 The incidence of adverse events was sim- crease of 1.7 kg) was statistically signifi- mmol/L for BIAsp 30 (Fig. 2B). IDegAsp ilar between IDegAsp and BIAsp 30 (65.6% cantly lower than with BIAsp 30 (increase was superior to BIAsp 30 in lowering FPG vs. 63.1%), with the majority being mild of 2.2 kg) (ETD 20.62 kg [95% CI 21.15 (ETD 21.14 mmol/L [95% CI 21.53 to to moderate in severity. Serious adverse to 20.10]). 20.76], P , 0.001). events were reported in 19 and 36 pa- After 26 weeks, mean SMPG levels Insulin Dose tients in the IDegAsp and BIAsp 30 treat- before breakfast (ETD 20.51 mmol/L Mean daily insulin dose after 26 weeks ment groups, respectively, the majority of [95% CI 20.88 to 20.14]), 90 min after was 1.08 units/kg for IDegAsp and 1.20 whom recovered completely. Two deaths 2088 IDegAsp in Insulin-Treated Type 2 Diabetes Diabetes Care Volume 37, August 2014

and headache. Injection site reactions were low in both treatment groups (IDegAsp, 0.4%; BIAsp 30, 0.9%: two events in each group). No clinically rel- evant differences were observed be- tween the two treatment groups with respect to physical examination find- ings, vital signs, standard laboratory analyses (hematology and biochemis- try), fundoscopy, or electrocardiogram.

CONCLUSIONS This confirmatory, randomized, con- trolled, 26-week, phase 3a trial demon- strated the efficacy and safety of IDegAsp BID, with or without concomi- tant OADs, in the treatment of patients with type 2 diabetes inadequately con- trolled on premixed or self-mixed insulin regimens OD or BID. IDegAsp provided effective overall glycemic control that was noninferior and comparable with that of BIAsp 30, with both treatments achieving clinically meaningful im- provements in HbA1c of ;1.3% points. Moreover, IDegAsp demonstrated su- perior reductions in FPG for IDegAsp, in combination with an 11% lower mean end of trial dose compared with BIAsp 30. The efficacy of IDegAsp is further sup- ported by the results from the nine- point SMPG profile reported in the current trial, with significantly lower mean PG levels at end of trial and sig- nificantly lower PG levels at three out of the nine time points: before breakfast, 90 min after breakfast, and before breakfast the following day. The treat- ment differences in FPG and prebreak- fast SMPG indicate that IDegAsp provides full 24-h basal coverage com- paredwithBIAsp30. Importantly, the greater reduction in FPG was accompanied by reductions in confirmed (32%), nocturnal confirmed (73%), and severe (50%) hypoglycemia, verifying previous findings of a lower risk of IDegAsp to cause hypoglycemia compared with premixed insulin (18). The percentage of patients achieving HbA1c ,7% without hypoglycemia in the previous 12 weeks was greater for Figure 2—Clinical end points. A:MeanHbA1c over time. B: Mean FPG over time. C: Cumulative rate of confirmed hypoglycemic episodes. D: Cumulative rate of nocturnal confirmed hypogly- IDegAsp versus BIAsp 30 (Supplemen- cemic episodes. tary Fig. 1). Furthermore, the differ- ences in hypoglycemia rates in favor of IDegAsp (39%, 77%, and 89% reduction were reported in this trial (interstitial lung The most frequent adverse events in in overall confirmed, nocturnal con- disease in the IDegAsp group and head both treatment groups were nasopha- firmed, and severe hypoglycemic epi- injury in the BIAsp 30 group). ryngitis, upper–respiratory tract infection, sodes, respectively, compared with care.diabetesjournals.org Fulcher and Associates 2089

Table 2—Hypoglycemic episodes in the IDegAsp and BIAsp 30 groups IDegAsp BID BIAsp 30 BID Participants Participants Rate: Rate: Estimated RR (95% CI): n % Episodes PYE n % Episodes PYE IDegAsp/BIAsp 30 P Safety analysis set: entire trial period Severe 7 3.1 9 0.09 16 7.2 25 0.25 0.50 (0.19–1.30) NS Overall confirmed 148 66.1 993 9.72 153 68.9 1,379 13.96 0.68 (0.52–0.89) 0.0049 Nocturnal confirmed 52 23.2 76 0.74 80 36.0 250 2.53 0.27 (0.18–0.41) ,0.0001 Patients in safety analysis set with at least 16 weeks of exposure: maintenance period (16 weeks to end of treatment) Severe 1 0.5 1 0.03 10 5.2 13 0.36 0.11 (0.01–0.91) 0.04 Overall confirmed 104 51.7 362 9.51 113 58.9 550 15.20 0.61 (0.45–0.83) 0.0015 Nocturnal confirmed 21 10.4 27 0.71 47 24.5 109 3.01 0.23 (0.13–0.41) ,0.0001 NS, not significant; PYE, patient-year of exposure.

BIAsp 30) are more pronounced during use of premixed insulin. However, phar- bureaus for Novo Nordisk, Boehringer Ingelheim, the maintenance period of treatment macodynamic studies have shown that and MSD. J.S.C. has served on advisory panels ’ (after $16 weeks of exposure when sta- premixed insulin does not provide 24 h and speakers bureaus for Novo Nordisk. G.B. has undertaken paid lecturing for Novo Nordisk. ble glycemic control and insulin dose glycemic control in all patients and, M.P.-M. has received research support from have been achieved), which represents moreover, is associated with higher var- Novo Nordisk, MSD, and Johnson & Johnson. the majority of a patients’ treatment iability and a lack of sustained and stable H.M. is an employee and shareholder of Novo time in clinical practice (Supplementary glucose infusion rate profile (23). On the Nordisk. T.H.A. is an employee of Novo Nordisk. No other potential conflicts of interest relevant Tables 2 and 3). other hand, basal-bolus insulin therapy to this article were reported. The observed lower hypoglycemic requires multiple daily injections and Author Contributions. G.R.F. designed the risk with IDegAsp is likely related to its frequent blood glucose measurements study, performed the research, and edited the pharmacodynamic profile, which con- and, hence, is a more complex treat- manuscript. J.S.C. designed the study and sists of a distinct prandial action and ment regimen. Use of a “basal plus” reg- contributed to the manuscript. G.B. performed fl the research. M.P.-M. contributed to the man- a separate, at, and stable glucose- imen (involving basal insulin and uscript. H.M. designed the study, analyzed data, lowering effect. This is in contrast to addition of a single bolus insulin injec- and edited the manuscript. T.H.A. contributed the glucose infusion profile of BIAsp tion) has recently demonstrated similar to the manuscript and analyzed data. L.K.N. performed the research and contributed to the 30, which is a formulation containing HbA1c control with improved FPG, less soluble (30%) and protaminated (70%) weight gain, lower rates of hypoglyce- manuscript. G.R.F. is the guarantor of this work and, as such, had full access to all the data in IAsp. Protaminated IAsp in BIAsp 30 mia, and lower total daily insulin use the study and takes responsibility for the exhibits an initial peak followed by a compared with twice-daily premixed integrity of the data and the accuracy of the gradual decline, falling below detect- insulin in insulin-naive patients (24). data analysis. able levels ;20 h postdose (14). The Similar benefits are demonstrated for References basal component of IDegAsp has been IDegAsp versus BIAsp 30 in the current 1. Inzucchi SE, Bergenstal RM, Buse JB, et al.; demonstrated in publication and highlight, in insulin- American Diabetes Association (ADA); Euro- studies to have an ultralong duration experienced patients, the advantage of pean Association for the Study of Diabetes of action, exceeding 42 h (14). There- full 24-h basal coverage and distinct (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position fore, IDegAsp provides full 24-h cover- rapid-acting mealtime coverage with statement of the American Diabetes Association age of basal insulin requirements as the additional simplicity of being com- (ADA) and the European Association for the shown by a distinct peak action due to bined in a single injection. This may help Study of Diabetes (EASD). Diabetes Care 2012; prandial IAsp and separate and stable to address the commonly cited issues of 35:1364–1379 2. Holman RR, Farmer AJ, Davies MJ, et al.; 4-T basal action from IDeg (20). The low complexity and inconvenience as bar- fi fi Study Group. Three-year ef cacy of complex in- variability of the IDeg component re- riers to timely insulin intensi cation sulin regimens in type 2 diabetes. N Engl J Med ported at steady state over a 24 h period (22) without the need to compromise 2009;361:1736–1747 (12,21) could further contribute to the prandial or basal insulin coverage in pa- 3. Ross SA, Tildesley HD, Ashkenas J. Barriers to low rates of hypoglycemia observed tients with type 2 diabetes. effective insulin treatment: the persistence of with IDegAsp. poor glycemic control in type 2 diabetes. Curr Med Opin 2011;27(Suppl. 3):13–20 Basal insulin and premixed insulin are 4.WildD,vonMaltzahnR,BrohanE, the most common treatment regimens Duality of Interest. Medical writing support Christensen T, Clauson P, Gonder-Frederick L. used when initiating insulin treatment in was provided by ApotheCom ScopeMedical Ltd A critical review of the literature on fear of hy- patients with type 2 diabetes (22). Cur- and funded by Novo Nordisk A/S. This study was poglycemia in diabetes: Implications for diabe- fi funded by Novo Nordisk A/S. G.R.F. has served tes management and patient education. Patient rently, when insulin intensi cation is re- on advisory panels for Novo Nordisk, Janssen, Educ Couns 2007;68:10–15 quired (to provide sufficient prandial Boehringer Ingelheim, and Merck Sharp & 5. Nathan DM, Buse JB, Davidson MB, et al.; coverage) this is often achieved through Dohme (MSD) and has served on speakers’ American Diabetes Association; European 2090 IDegAsp in Insulin-Treated Type 2 Diabetes Diabetes Care Volume 37, August 2014

Association for Study of Diabetes. Medical Hagedorn cartridges. J Diabetes Sci aspart 30 in type 2 diabetes: a randomised trial. management of hyperglycemia in type 2 dia- Tech 2010;4:652–657 Eur J Endocrinol 2012;167:287–294 betes: a consensus algorithm for the initiation 13. Havelund S, Ribel U, Hubalek´ F, et al. Insulin 19. International Conference on Harmonisation of and adjustment of therapy: a consensus state- degludec (IDeg) and insulin aspart (IAsp) can be Technical Requirements for Registration of Phar- ment of the American Diabetes Association co-formulated such that the formation of IDeg maceuticals for Human Use Guideline for Good and the European Association for the Study multi-hexamers and IAsp monomers is retained Clinical Practice guidelines. Available from http:// of Diabetes. Diabetes Care 2009;32:193–203 upon s.c. injection (Abstract). Diabetes 2013;62 www.ich.org/fileadmin/Public_Web_Site/ICH_ 6. Vijan S, Hayward RA, Ronis DL, Hofer TP. Brief (Suppl. 1):A241 Products/Guidelines/Efficacy/E6_R1/Step4/ report: the burden of diabetes therapy: impli- 14. Heise T, Nosek L, Hastrup H, et al. IDegAsp E6_R1__Guideline.pdf. Accessed 11 April 2014 cations for the design of effective patient- shows distinct prandial and basal glucose- 20. Heise T, Nosek L, Klein O, et al. IDegAsp centered treatment regimens. J Gen Intern lowering effects at steady state in subjects produces dose-proportional glucose-lowering Med 2005;20:479–482 with (Abstract). Diabetes 2013; effect in subjects with type 1 diabetes (Ab- 7. Garber AJ, Ligthelm R, Christiansen JS, Liebl 62(Suppl. 1):A235 stract). Diabetes 2013;62(Suppl. 1):A241 A. Premixed insulin treatment for type 2 diabe- 15. Heise T, Nosek L, Bøttcher SG, Hastrup H, 21. Kurtzhals P, Heise T, Strauss HM, et al. tes: analogue or human? Diabetes Obes Metab Haahr H. Ultra-long-acting insulin degludec Multi-hexamer formation is the underlying ba- 2007;9:630–639 has a flat and stable glucose-lowering effect in sis for the ultra-long glucose-lowering effect of 8. Liebl A, Prusty V, Valensi P, et al. Ten years of type 2 diabetes. Diabetes Obes Metab 2012;14: insulin degludec (Abstract). Diabetologia 2011; experience with biphasic insulin aspart 30: from 944–950 54:A1049 drug development to the latest clinical findings. 16. Ratner RE, Gough SC, Mathieu C, et al. Hy- 22. Vaag A, Lund SS. Insulin initiation in pa- Drugs 2012;72:1495–1520 poglycaemia risk with insulin degludec com- tients with type 2 diabetes mellitus: treatment 9. Leiter LA, Yale J-F, Chiasson J-L, et al. Assess- pared with insulin glargine in type 2 and type guidelines, clinical evidence and patterns of use ment of the impact of fear of hypoglycemic 1 diabetes: a pre-planned meta-analysis of of basal vs premixed insulin analogues. Eur J episodes on glycemic and hypoglycemia man- phase 3 trials. Diabetes Obes Metab 2013;15: Endocrinol 2012;166:159–170 agement. Can J Diabetes 2005;29:186–192 175–184 23. Heise T, Nosek L, Coester HV, et al. Insulin 10. Peyrot M, Barnett AH, Meneghini LF, 17. Meneghini L, Atkin SL, Gough SC, et al.; degludec/insulin aspart produces a dose- Schumm-Draeger PM. Insulin adherence behav- NN1250-3668 (BEGIN FLEX) Trial Investigators. proportional glucose-lowering effect in subjects iours and barriers in the multinational Global The efficacy and safety of insulin degludec given with type 1 diabetes. International Diabetes Fed- Attitudes of Patients and Physicians in Insulin in variable once-daily dosing intervals com- eration, 2–6 December 2013, poster P-1400 Therapy study. Diabet Med 2012;29:682–689 pared with insulin glargine and insulin degludec 24. Riddle MC, Rosenstock J, Vlajnic A, Gao L. 11. Jonassen I, Hoeg-Jensen S, Havelund S, dosed at the same time daily: a 26-week, ran- Randomized, 1-year comparison of three Ribel U. Ultra-long acting insulin degludec can domized, open-label, parallel-group, treat-to- ways to initiate and advance insulin for type 2 be combined with rapid-acting insulin aspart target trial in individuals with type 2 diabetes. diabetes: twice-daily premixed insulin versus in a soluble co-formulation (Abstract). J Pept Diabetes Care 2013;36:858–864 basal insulin with either basal-plus one prandial Sci 2010;16(Supp. 1):A380 18. Niskanen L, Leiter LA, Franek E, et al. Com- insulin or basal-bolus up to three prandial in- 12. Kaiser P, Maxeiner S, Weise A, et al. Assess- parison of a soluble co-formulation of insulin jections. Diabetes Obes Metab 2014;16:396– ment of the mixing efficiency of neutral degludec/insulin aspart vs biphasic insulin 402