A New Option for Glycemic Control: Insulin Degludec, a New-Generation Basal Insulin with an Ultralong Duration of Action

Transcription

1 A New Option for Glycemic Control: Insulin Degludec, a New-Generation Basal Insulin with an Ultralong Duration of Action Scott R. Drab 1,2, * and Athena Philis-Tsimikas 3 1 University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; 2 University Diabetes Care Associates, Pittsburgh, Pennsylvania; 3 Scripps Whittier Diabetes Institute-Scripps Health, La Jolla, California Basal insulin represents an essential tool in the treatment of diabetes mellitus; it can be prescribed with oral antidiabetic agents for the management of type 2 diabetes (T2D) or used as part of a basal-bolus regimen in type 1 diabetes (T1D) and more advanced T2D. The basal insulin products currently on the market, although improved, do not optimally mimic endogenous insulin secretion. It is therefore important to investigate how the action of a basal insulin can be improved to match the physiologic profile more precisely and consequently to examine the desired properties of an ideal new-generation basal insulin. Some of these characteristics would include stable pharmacokinetic (PK) and pharmacodynamic (PD) profiles, true 24-hour duration of action in all patients, low within-person variability in absorption and glucose-lowering action, more flexible dose timing, and low occurrence of hypoglycemia. A new-generation basal insulin, insulin degludec, currently approved in Japan, Mexico, and Europe, was designed to provide a more stable pharmacotherapeutic option with a lower risk of hypoglycemia than the currently available basal insulins while retaining an efficacious profile. The characteristics of an ideal basal insulin are reviewed, and the pharmacology and clinical attributes of insulin degludec are discussed. KEY WORDS insulin degludec, basal insulin, diabetes, hypoglycemia, ultralong-acting insulin. (Pharmacotherapy 2014;34(3): ) doi: /phar.1361 Insulin degludec (IDeg) was selected from a series of acylated insulins created by adding various fatty acid or fatty diacid side chains to the Lys B29 residue of biosynthetic desb30 human insulin. 1 The molecular structure of IDeg includes a hexadecandioyl-l-c-glu side chain (Figure 1) 2 that enables IDeg, in the presence of zinc and phenol in formulation, to self-associate into stable, soluble dihexamers. After injection into the subcutaneous tissue, phenol disperses, allowing these dihexamers to self-associate Medical writing and editorial assistance were supported by Novo Nordisk. *Address for correspondence: Scott R. Drab, University of Pittsburgh School of Pharmacy, 719 Salk Hall, Pittsburgh, PA 15261; drab@pitt.edu. Ó 2013 American College of Clinical Pharmacy quickly into larger chain-like, soluble multihexamers. 1 Individual insulin molecules then gradually dissociate from the ends of the multihexamers, to be released as monomers at a constant slow rate into the circulation. This allows for steady and gradual absorption of insulin with zero-order kinetics to produce a constant blood glucose-lowering action. Furthermore, this method of prolonged absorption and release gives IDeg an ultralong duration of action, with a half-life of more than 25 hours 3, 4 and a duration of action extending beyond 42 hours. 5 A full understanding of this protraction mechanism requires some knowledge of the human insulin structure and the modifications that were made to engineer the IDeg molecule. Insulin naturally self-associates into dimers that in the presence of zinc further associate into hexamers

2 292 PHARMACOTHERAPY Volume 34, Number 3, 2014 consisting of three insulin dimers surrounding two zinc ions (Zn 2+ ) in the core of the molecule (Figure 2). Insulin hexamers can exist in three different conformational states, depending on S G I V E Q C C T S I C S L Y Q L E N Y C N A-chain S S S F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K B-chain HO desb30 insulin O S S Hexadecandioyl O N H O O NH OH L-γ-Glu Figure 1. The structure of insulin degludec. Insulin degludec was formed by linking a hexadecandioyl-l-c-glu residue to the B-chain of biosynthetic human desb30 insulin. The fatty acid moiety plays a large role in the ultralong duration of action of IDeg because it allows dihexamers to link up and form chains. (Reproduced with permission from reference 2.) the relative positions adopted by some of the terminal amino acid residues on the B chain of each insulin monomer. 6, 7 These three configurations are a relaxed state (R), in which the core of the hexamer is shielded at both poles (R 6 ); a tense state (T), in which the core is exposed at both poles (T 6 ); and an intermediate state, in which the core is exposed at one pole and shielded at the other (T 3 R 3 ). When both poles of the hexamer are closed, Zn 2+ and amino acids located in the center of the hexamer are prevented from interacting with other molecules. However, when at least one pole is open, interactions with other molecules can potentially occur. In the case of IDeg, a fatty diacid side chain from one hexamer can interact with a Zn 2+ in the core of another hexamer to form dihexamers, and when both poles are open, this can lead to formation of long multihexamer chains. 1 In the presence of sufficient phenol (as occurs in the pharmaceutical formulation), the hexamer poles of human insulin close (R state). However, in the case of IDeg, which does not take on the Top Side view Dimer Monomer Base Cl Insulin hexamer (R 6 -state) Insulin hexamer (T 3 R 3 -state) Insulin hexamer (T 6 -state) Zn 2+ Phenol Figure 2. Insulin naturally self-associates into dimers, which in the presence of zinc further associate into hexamers consisting of three insulin dimers surrounding two zinc ions (Zn 2+ ) in the core of the molecule. Insulin hexamers can exist in three different conformational states: a relaxed state, in which the core of the hexamer is shielded at both poles (R 6 ); a tense state, in which the core is exposed at both poles (T 6 ); and an intermediate state, in which the core is exposed at one pole and shielded at the other (T 3 R 3 ). (Adapted with permission from reference 1.)

3 INSULIN DEGLUDEC Drab and Philis-Tsimikas 293 R state, one pole closes and the other remains open (T 3 R 3 conformation); hence IDeg hexamers are able to link together as dihexamers. This structure is highly stable and resistant to interactions with other compounds or further aggregation. Immediately after subcutaneous injection, phenol is rapidly depleted, and the IDeg dihexamers take on the T 6 conformation, in which the center of the hexamer is exposed with both poles open, allowing Zn 2+ and amino acids located within to interact with other IDeg dihexamers and to form long multihexamer chains in the subcutaneous tissue, as just described. 1 Due to their size, these are unable to enter the circulation, thereby prolonging the absorption rate. Eventually, with the gradual depletion of zinc, the hexamers located at the ends of the large molecular chain sequentially dissociate, thus resulting in slow and continuous release of insulin monomers or dimers that rapidly break apart into monomers. These smaller molecules are then able to penetrate the capillary system, thus allowing the distribution of IDeg throughout the body and subsequent signaling at the insulin receptor. For IDeg, reversible plasma albumin binding to the fatty acid moiety may also provide an additional secondary mechanism of protraction. The affinity for albumin is likely to buffer any variability that does occur in absorption rate through the mechanism described previously by Kurtzhals. 8 Properties of an Ideal Basal Insulin The two currently available basal insulin analogs insulin glargine (IGlar) and insulin detemir (IDet) represent an improvement over previous generation intermediate- and longacting human insulin products. However, they do not fully meet all of the desired criteria for an ideal basal insulin. Desired improvements include the following: a flatter glucose-lowering profile, a longer duration of action, decreased variability in absorption and glucose-lowering action, ability to be coformulated with rapid-acting insulin analogs, and no signal of increased mitogenic activity. 9 Stable Pharmacokinetic and Pharmacodynamic Profiles The goal of basal insulin supplementation or replacement therapy is to approximate the constant plasma level of insulin arising from endogenous insulin secretion during fasting (e.g., overnight and between widely spaced meals). Long-acting basal insulin formulations aim to mimic the endogenous insulin response through the continuous release of low concentrations of insulin from the injection site over an extended period of time. To provide a constant blood glucose-lowering effect (e.g., one that does not wax and wane throughout the day), it is desirable that basal insulins exhibit stable steady-state PK and PD profiles. The profiles of glucose-lowering action of both IDet and IGlar are characterized by a gentle rise and fall within a 24-hour period, without a pronounced peak. 10 Although the PK and PD properties of IGlar and IDet more closely resemble the endogenous insulin profile than those of previously developed intermediate- and longacting human insulins, their profiles still leave room for further improvement with respect to a smooth peakless profile as well as a true 24-hour duration of action in all patients (Figure 3). 11 Minimal Variability in Absorption and Blood Glucose-Lowering Action The PK and PD profiles of a basal insulin should ideally not only be flat and stable, but also be reproducible; each administration of insulin should result in similar absorption rates and blood glucose-lowering effects for an individual person. Although within-person variability has improved with the development of new basal insulin analogs IDet and IGlar 10, 11 (Figure 3), improving the reproducibility of the PD profile could maximize the overall glucose-lowering potential for the basal insulin. The profile of blood glucose-lowering action has been shown to vary from injection to injection with IGlar, and with IDet. 11, 12 This variability could compromise patients ability to reliably titrate dosing more precisely to reach target fasting glucose values. For example, if atypically slow absorption occurs, this can result in periods of hyperglycemia; conversely, unusually rapid absorption can cause an unexpected drop in glucose levels and subsequent hypoglycemia. In addition to the well-known detrimental physiologic effects of hyperglycemia and hypoglycemic episodes, fear of hypoglycemia greatly limits willingness to strive for tight glycemic targets and has been shown to influence a person s quality of life adversely. 13 Therefore, minimizing variability in absorption and action is an important property of an ideal basal insulin.

4 294 PHARMACOTHERAPY Volume 34, Number 3, 2014 NPH insulin Insulin glargine Insulin detemir Glucose infusion rate (mg/kg/min) Time (hours) Figure 3. Glucose-lowering effect over 24 hours of NPH insulin, insulin glargine, and insulin detemir. Both insulin glargine and insulin detemir have a flatter and more constant glucose-lowering profile than NPH insulin. (Adapted with permission from reference 11.) Long Duration of Action for Greater Dosing Flexibility Greater freedom in daily insulin dosing has become increasingly important, especially when considering the busy lifestyles of a large proportion of people with diabetes mellitus. 14, 15 In addition, individuals with erratic work schedules or those who frequently travel could potentially benefit from the ability to take their insulin at a time suitable to them, providing this could be done without compromising glycemic control or increasing risk of hypoglycemia. However, greater flexibility in dosing depends critically on having a sufficiently prolonged duration of action in which a steady-state profile is achieved, limiting the effect of varying dosing times on peak and trough insulin values, compared with an insulin that would be fully absorbed within a 24-hour period. 4 Unlike a rapid-acting insulin, for which a shorter action profile and rapid elimination is optimal, the goal with a long-acting basal insulin administered once/day is to achieve a stable steady-state concentration so that the amount available in circulation is predictable and constant over a 24-hour period. The duration of action of the two currently available long-acting basal insulin analogs has been extended through two different mechanisms. IGlar is soluble at low ph (ph 4.0) in formulation; on exposure to neutral ph after injection, it becomes less soluble, forming microprecipitates at the injection site from which slow dissolution occurs. By comparison, IDet self-associates into hexamers via fatty acid chains and reversibly binds to albumin at the site of the injection and in circulation. 16 The duration of action for IDet and IGlar is nearly 24 hours in people with T1D and can exceed 24 hours in people with T2D. 10 As would be expected for a long-acting insulin dosed to steady state, neither of these insulins have shown any evidence of unwanted accumulation, and indeed both have been shown to have a decreased risk of hypoglycemia versus NPH insulin in clinical studies. 9 However, neither of these insulins achieves the ideal profile of an ultralong duration of action (e.g., well in excess of 24 hours) in all patients and at all dose ranges. 9 Opportunities for Coformulation The ability to coformulate a basal and a rapidacting insulin would lower the number of required daily injections in a basal-bolus regimen

5 INSULIN DEGLUDEC Drab and Philis-Tsimikas 295 or enable some control of both fasting and postprandial glucose levels with a single injection. One major limitation of current basal insulin analogs is that they cannot be mixed and kept in pharmaceutical formulation with rapidacting insulins. IGlar would result in precipitation within the injection device if mixed with rapid-acting insulin. By contrast, IDet is soluble, but mixing with a rapid-acting analog could result in a lowered and delayed maximum glucose-lowering effect of the rapid-acting component, which would be undesirable. 9 The ideal basal insulin would thus have properties that allowed a combination with rapid-acting insulin in the same injection device while retaining the PK and PD characteristics of each insulin. Low Mitogenic Potential Insulin has some ability to bind and activate the insulin-like growth factor (IGF)-1 receptor on cells and thereby stimulate cell division, 17 although its affinity for the insulin receptor is orders of magnitude greater than that for the IGF- 1 receptor A concern when analogs of insulin are engineered, however, is that they might inadvertently have an increased relative affinity for the IGF-1 receptor, potentially leading to unwanted proliferative effects that could accelerate tumor growth. Examining the proliferative potential of newly developed insulins relative to human insulin is therefore important, and having a minimal mitogenic potential in vitro should be a desirable attribute of any new insulin. It should be remembered that the risk benefit ratio for insulin treatment in general remains excellent, 21 although questions have been raised about whether insulin analogs could contribute to the increased risk of cancer that is observed in people with diabetes Recent results from a trial involving 6264 people treated with IGlar for a median follow-up of 6.2 years showed no significant difference in the incidence of cancer (p=0.97) or death from cancer (p=0.52) compared with those receiving standard care. 27 Nevertheless, a basal insulin that has no signal of increased mitogenic activity may give an added measure of assurance for its safety. Pharmacokinetic and Pharmacodynamic Profiles of Insulin Degludec Despite the promising molecular qualities of IDeg, these alone cannot give any insight into whether this insulin can more closely achieve the characteristics of the ideal basal insulin described here. However, PK and PD studies in people with T1D and T2D can provide valuable data and clinical insight. The in vivo euglycemic clamp technique (clamp study) is the standard for assessing the PD profile of insulin. 10 In these studies, blood glucose is stabilized via intravenous infusion several hours before beginning the study. Insulin is then injected, and investigators strive to maintain blood glucose at a prespecified target level through a continuous glucose infusion. The glucose infusion rate time curve required to resist the blood glucose-lowering action of the insulin by maintaining the target level in this experimental situation thus becomes a measure for the PD profile. Plasma insulin can also be measured by using serial venous blood samples to assess PK. Flat and Stable Steady-State Pharmacokinetic Profile The PK profile of IDeg at three different doses (0.4, 0.6, or 0.8 U/kg once/day) was examined by using a euglycemic clamp study in 49 subjects with T2D. 4 IDeg exposure (AUC IDeg,s,SS ) increased with an increasing dose of IDeg (89,643.2 pmolh/l with 0.4 U/kg, 130,164 pmolh/l with 0.6 U/kg, and 177,408 pmolh/l with 0.8 U/kg) [Correction added after online publication 17-Oct-2013: 177,407 pmolh/l has been updated as 177,408 pmolh/l.]. Steady state was reached after 2 3 days in all subjects. Exposure to IDeg was distributed evenly over the 24-hour dosing interval; the AUC I- Deg, 0 12 h,ss as a percentage of AUCIDeg,s,SS was 53.3, 52.5, and 52.7 for 0.4, 0.6, and 0.8 U/kg, respectively. The respective half-lives (t 1/2,IDeg,SS ) were 24.6, 24.4, and 26.8 hours. Further PK data have been reported in abstract form. To establish the PK parameters of IDeg in T1D, the insulin concentration in the blood of 66 adults given 0.4, 0.6, or 0.8 U/kg IDeg once/day was measured over several days. 3 IDeg exhibited a mean half-life of 25.4 hours at all three doses, whereas that of the comparator, IGlar, was 12.5 hours. These results suggest that IDeg is slowly and continuously released and absorbed into the circulation as intended. In addition, similar PK profiles for IDeg have been observed in children and adolescents with T1D. 28 Such a flat and extended PK profile, which should result in a constancy of the glucose-lowering effect, is key to adding more flexibility and adapting insulin dosing to a patient s lifestyle. Furthermore, there do not appear to be any alterations in this PK profile in subjects with

6 296 PHARMACOTHERAPY Volume 34, Number 3, 2014 GIR (mg/kg/min) Time (h) 0.8 U/kg 0.6 U/kg 0.4 U/kg Figure 4. Glucose-lowering effect of insulin degludec in patients with type 2 diabetes mellitus. In a glucose clamp study, the glucose-lowering effect of insulin degludec was evenly distributed between the first and second 12 hours for all three dose levels (AUC GIR,0 12 h,ss /AUC GIR,total,SS = 0.5). AUC = area under the GIR time curve; GIR = glucose infusion rate; SS = steady state. (Reproduced with permission from reference 4.) either hepatic 29 or renal impairment (including dialysis), 30 or in elderly subjects with T1D. 31 Stable and Consistent Glucose-Lowering Effect In a double-blind randomized parallel-group study of 54 people with T1D receiving 0.4 U/kg once/day of either IDeg or IGlar over 12 days, euglycemic clamp analysis showed that after 12 days (by which time steady state was established), IDeg exhibited a flat and stable PD profile. 32 Additionally, within-person variability in the PD profile was four times lower with IDeg than with IGlar. 32 Similar euglycemic clamp studies in people with T2D were also performed using varying doses (0.4, 0.6, or 0.8 U/kg once/day) of IDeg, and these showed that the blood glucoselowering properties of this insulin were flat and stable irrespective of dose (Figure 4). 4 Glucose lowering also appears to be consistent for black, white, and Hispanic-Latino subjects 33 and independent of subcutaneous injection region. 34 Safety and Efficacy Considerations IDeg safety and efficacy results were published from two 16-week phase II studies, one in people with T1D using a basal-bolus regimen 35 and the other in people with T2D using a basal insulin plus metformin regimen. 36 Table 1 summarizes the findings from these and other IDeg clinical trials These phase II trials were consistent in showing that IDeg expectedly achieved similar improvements in glycemic control to IGlar but with reduced rates of hypoglycemia. Data have now been reported from larger scale phase III treat-to-target trials of longer duration. With the treat-to-target design, all randomized participants titrate insulin to reach a predetermined glucose target. This approach facilitates a more interpretable risk benefit ratio with respect to efficacy and hypoglycemic events. Three 52-week randomized controlled phase II studies (one in people with T1D, 37 two in people with T2D 39, 40 ) have been published, two of which compared IDeg and IGlar in a basal-bolus regimen including insulin aspart (IAsp) 37, 39 and another compared IDeg or IGlar, both in conjunction with oral antidiabetic drugs, in insulin-naive people with T2D. 40 Three 26-week phase III studies, all conducted in insulin-naive T2D populations, have also been published. One compared IDeg and IGlar in an Asian population, 42 one compared IDeg and the oral antidiabetic drug sitagliptin, 43 and one evaluated a more concentrated 200-U/ml formulation of IDeg versus IGlar. 44 Finally, two 26-week phase III studies (discussed later) examined the effect of a flexible dosing regimen of IDeg compared with IGlar given according to label in people with T2D 41 and T1D. 38 In the 52-week studies conducted in people with T1D 37 and T2D, 39 basal-bolus therapy with IDeg or IGlar effectively reduced hemoglobin A 1c (A1C) levels to a similar extent, but the proportion of people reporting nocturnal hypoglycemia was lower for IDeg (Table 1). In addition, overall confirmed hypoglycemia was less frequent with IDeg than with IGlar in people with T2D. 39 Therefore, basal-bolus therapy with IDeg exhibits a superior safety profile compared with IGlar while providing effective glycemic control. In the basal insulin plus oral antidiabetic drug trial, IDeg and IGlar reduced A1C to a similar extent, and overall rates of confirmed hypoglycemia were comparable. 40 Nocturnal hypoglycemic events were uncommon and occurred significantly less frequently with IDeg compared with IGlar (p=0.038). When compared with sitagliptin, IDeg provided superior glycemic control and had a similar rate of nocturnal hypoglycemic events, but the rate of overall hypoglycemia was greater with IDeg. 43 When these trials were designed and conducted, there were no guidelines from official organizations about how to define hypoglycemia in research studies. Indeed, landmark treat-totarget trials of insulin in people with T2D that compared once/day IGlar plus oral antidiabetic drugs with insulin premix, 45 NPH, 46 and

7 Table 1. Published Clinical Trials of Insulin Degludec in Subjects with Types 1 and 2 Diabetes Mellitus Study design and population Treatment regimens Reported outcomes T1D studies 16-wk randomized open-label trial in people with T1D 35, a 52-wk, randomized open-label, treat-to-target trial in people with T1D wk randomized open-label, treat-to-target trial in people with T1D, with a 26-wk extension preceded by a washout period 38, b T2D studies 16-wk randomized open-label, parallel-group trial in people with T2D 36, a 52-wk randomized treat-totarget, open-label trial in people with T2D 39 INSULIN DEGLUDEC Drab and Philis-Tsimikas subjects randomized to IDeg once/day (n=59) or IGlar once/day (n=59) Both regimens included IAsp at mealtimes 629 subjects randomized to basal-bolus therapy with either IDeg once/day (n=472) or IGlar once/day (n=157) Both regimens included IAsp at mealtimes 164 subjects randomized to IDeg ForcedFlex, 164 subjects to IGlar once/ day, and 165 subjects to IDeg once/day during wks 0 26; after 26 wks, 329 subjects previously randomized to either IDeg regimen were switched to IDeg FreeFlex for another 26 wks All regimens included IAsp at mealtimes 122 subjects randomized to IDeg once/day (n=60) or IGlar once/day (n=62) in combination with metformin 992 subjects randomized to basal-bolus therapy with either IDeg once/day (n=744) or IGlar once/day (n=248) metformin pioglitazone Both regimens included IAsp at mealtimes A1C reduction: ETD, IDeg IGlar: 0.10% points (95% CI 0.14 to 0.34%]) FPG reduction: ETD, IDeg IGlar: 10.1 (95% CI 33.2 to 13.2) mg/dl Rate of confirmed hypoglycemia: RR, IDeg vs IGlar: 0.72 (95% CI ) Rate of nocturnal hypoglycemia: RR, IDeg vs IGlar: 0.42 (95% CI ) A1C reduction: ETD, IDeg IGlar: 0.01% points (95% CI 0.14 to 0.11%), p< FPG reduction: ETD, IDeg IGlar: 5.9 (95% CI 18.6 to 6.5) mg/dl, p=0.35 Rate of confirmed hypoglycemia: ERR, IDeg vs IGlar: 1.07 (95% CI ), p=0.48 Rate of nocturnal hypoglycemia: ERR, IDeg vs IGlar: 0.75 (95% CI ), p=0.021 A1C reduction: ETD, IDeg ForcedFlex IGlar: 0.17% points (95% CI %) ETD, IDeg ForcedFlex IDeg once/day: 0.01% points (95% CI 0.13 to 0.14%) ETD, IDeg FreeFlex IGlar: 0.08% points (95% CI 0.06 to 0.22%) FPG reduction: ETD, IDeg ForcedFlex IGlar: 0.90 (95% CI 15.3 to 13.7) mg/dl, p=ns ETD, IDeg ForcedFlex IDeg once/day: 17.1 (95% CI ) mg/dl, p=0.021 ETD, IDeg FreeFlex IGlar: 19.3 (95% CI 32.8 to 5.8) mg/dl, p=0.005 Rate of confirmed hypoglycemia: ERR, IDeg ForcedFlex vs IGlar: 1.03 (95% CI ), p=ns; ERR, IDeg ForcedFlex vs IDeg once/day: 0.92 (95% CI ), p=ns; ERR, IDeg FreeFlex vs IGlar: 1.02 (95% CI ), p=ns Rate of nocturnal hypoglycemia: ERR, IDeg Forced Flex vs IGlar: 0.60 (95% CI ) p=0.001; ERR, IDeg Forced Flex vs IDeg once/day: 0.63 (95% CI ), p=0.003; ERR, IDeg FreeFlex vs IGlar: 0.73 (95% CI ), p=0.035 A1C reduction: ETD, IDeg IGlar: 0.17% points (95% CI 0.15 to 0.48%) FPG reduction: ETD, IDeg Glar: 1.62 (95% CI 17.5 to 14.2) mg/dl Rate of confirmed hypoglycemia: ERR, IDeg vs IGlar: 0.44 (95% CI ) A1C reduction: ETD, IDeg IGlar: 0.08% points (95% CI 0.05 to 0.21) FPG reduction: ETD, IDeg IGlar: 5.2 (95% CI 11.7 to 1.1) mg/dl Rate of confirmed hypoglycemia: ERR, IDeg vs IGlar: 0.82 (95% CI ), p= Rate of nocturnal hypoglycemia: ERR, IDeg vs IGlar: 0.75 (95% CI ), p= (continued)

8 298 PHARMACOTHERAPY Volume 34, Number 3, 2014 Table 1. (continued) Study design and population Treatment regimens Reported outcomes 52-wk, randomized open-label, treat-to-target, trial in insulin-naive people with T2D wk randomized open-label, treat-to-target trial in people with T2D wk randomized open-label, treat-to-target trial in insulin-naive Asians with T2D wk randomized open-label, treat-to-target trial in insulin-naive people with T2D wk randomized open-label, treat-to-target trial in insulin-naive people with T2D subjects randomized to either IDeg once/day (n=773) or IGlar once/day (n=257) + metformin dipeptidyl peptidase-4 inhibitor 687 subjects randomized to either IDeg Flex (n=229), IGlar once/day (n=230) or IDeg once/day (n=228) metformin sulfonylurea/glinides pioglitazone 435 subjects randomized to either IDeg once/day (n=289) or IGlar once/day (n=146) metformin sulfonylurea/ glinides a-glucosidase inhibitor 458 subjects randomized to either IDeg once/day (n=229) or sitagliptin (n=229) with 1 2 pretrial OADs 457 subjects randomized to either IDeg 200 U/ml once/day (n=228) or IGlar (n=229) once/day + metformin dipeptidyl peptidase-4 inhibitor A1C reduction: ETD, IDeg IGlar: 0.09% points (95% CI 0.04 to 0.22) FPG reduction: ETD, IDeg IGlar: 7.7 (95% CI 13.3 to 2.3) mg/dl, p=0.005 Rate of confirmed hypoglycemia: ERR, IDeg vs IGlar: 0.82 (95% CI ), p=0.106 Rate of nocturnal hypoglycemia: ERR, IDeg vs IGlar: 0.64 (95% CI ), p=0.038 A1C reduction: ETD, IDeg Flex IGlar: 0.04% points (95% CI 0.12 to 0.20); ETD, IDeg Flex IDeg once/day: 0.13% points (95% CI 0.29 to 0.03) FPG reduction: ETD, IDeg Flex IGlar: 7.6 (95% CI 14.8 to 0.4) mg/dl, p=0.04; ETD, IDeg Flex IDeg once/day: 0.90 (95% CI 8.1 to 6.3) mg/dl Rate of confirmed hypoglycemia: RR, IDeg Flex vs IGlar: 1.03 (95% CI ), p=ns; RR, IDeg Flex vs IDeg once/day: 1.10 (95% CI ), p=ns Rate of nocturnal hypoglycemia: RR, IDeg Flex vs IGlar: 0.77 (95% CI ), p=ns; RR, IDeg Flex vs IDeg once/day: 1.18 (95% CI ), p=ns A1C reduction: ETD, IDeg IGlar: 0.11% points (95% CI 0.03 to 0.24%) FPG reduction: ETD, IDeg IGlar: 1.6 (95% CI 7.4 to 4.1) mg/dl, p=0.59 Rate of confirmed hypoglycemia: RR, IDeg vs IGlar: 0.82 (95% CI ), p=0.20 Rate of nocturnal hypoglycemia: ERR, IDeg vs IGlar: 0.62 (95% CI ), p=0.07 A1C reduction: ETD, IDeg Sita: 0.43% points (95% CI 0.61 to 0.24); p< FPG reduction: ETD, IDeg Sita: 39.1 (95% CI 46.7 to 31.4) mg/dl, p< Rate of confirmed hypoglycemia: ERR, IDeg vs Sita: 3.81 (95% CI ), p< Rate of nocturnal hypoglycemia: ERR, IDeg vs Sita: 1.93 (95% CI ), p=0.09 A1C reduction: ETD, IDeg IGlar: 0.04% points (95% CI 0.11 to 0.19) FPG reduction: ETD, IDeg IGlar: 7.56 (95% CI 14.1 to 1.1) mg/dl, p=0.02 [Correction added after online publication 17-Oct-2013: p<0.02 has been updated to p=0.02.] Rate of confirmed hypoglycemia: RR, IDeg vs IGlar: 0.86 (95% CI ), p=0.46 Rate of nocturnal hypoglycemia: ERR, IDeg vs IGlar: 0.64 (95% CI ), p=0.25 A1C = hemoglobin A 1c ;CI= confidence interval; ERR = estimated rate ratio; ETD = estimated treatment difference; IDeg = insulin degludec; IDet = insulin detemir; IGlar = insulin glargine; NS = not significant; RR = rate ratio; T1D = type 1 diabetes; T2D = type 2 diabetes. a The results reported here only include data for the IDeg formulations and regimens to be marketed. b Data given here for the FreeFlex comparisons are 0 52 wk data reported for the extension trial set (i.e., the cohort that entered the extension study) except for FPG, which is only reported for 0 52 wks based on the original full analysis set (i.e., the intention-to-treat cohort). All 26-wk data reported for this study are based on the full analysis set. biphasic IAsp 70/30 47 have used different definitions for hypoglycemia, and none have specified an explicit time period for determining nocturnal episodes. In the IDeg clinical development program, the same definition of hypoglycemia was used in all studies: confirmed hypoglycemia

9 INSULIN DEGLUDEC Drab and Philis-Tsimikas 299 was an episode in which plasma glucose level was lower than 56 mg/dl irrespective of symptoms, and severe hypoglycemia was an event requiring assistance. Events occurring between 12:01 A.M. and 5:59 A.M. were classified as nocturnal, and those occurring between 06:00 A.M. and 12:00 midnight were diurnal. In a preplanned meta-analysis across seven trials (five in people with T2D and two in people with T1D), IDeg was associated with significantly lower rates of overall and nocturnal hypoglycemia compared with IGlar in people with T2D and significantly lower rates of nocturnal hypoglycemia in people with T1D (p<0.05 for all comparisons). 48 The reduction in nocturnal hypoglycemia in these studies is of interest because episodes during the nighttime are more likely to be attributable to the basal insulin than daytime episodes, for which the bolus insulin, food intake, and patient activity is more influential. The importance of sufficiently controlling nonsevere nocturnal hypoglycemia has recently been highlighted by a study that showed that nonsevere nocturnal hypoglycemia strongly influences a person s well-being and predisposes to absenteeism at work. 49 Because there could be concern because an ultralong duration basal insulin will naturally persist longer at the site of subcutaneous injection, local tolerability has also been examined. A meta-analysis of 4258 patients with T1D (two trials) or T2D (four trials) who received either IDeg (n=3060) or IGlar (n=1198) for 26 or 52 weeks showed that a similar and low proportion of patients reported injection-site reactions with IDeg (3.6%) or IGlar (3.5%). 50 These included injection-site hematoma, injection-site reaction (unspecific), and injectionsite pain. Few (0.1%) of the participants withdrew from trials due to injection-site reactions, indicating good local tolerability. Other Attributes of Insulin Degludec Other potential advantages of IDeg include the ability to coformulate it with rapid-acting insulins, flexibility in dosing, availability of a 200-U/ ml formulation, and low mitogenic signaling. With respect to the latter, the metabolic and mitogenic potencies of IDeg were analyzed in a number of cell lines. 51 In these in vitro studies, it was found that the kinetics of IDeg binding to the insulin receptor was similar to those of human insulin and lacked any sustained signaling. Furthermore, metabolic and mitogenic responses were similar to those of human insulin in four different cell lines, and the affinity ratio of IDeg for the IGF-1 receptor versus the insulin receptor was not increased relative to human insulin. Coformulation of Insulin Degludec with Insulin Aspart IDeg is the first basal analog insulin to have been successfully combined with a rapid-acting insulin (in this case, IAsp), and such a product is currently in clinical development in a coformulation of 70% IDeg and 30% IAsp (volume /volume) Until recently, when both postprandial and basal glucose controls were desired from a single injection, the only option was a premixed insulin, such as biphasic IAsp 70/30 or biphasic insulin lispro 50/50. Previously, the combination of basal and rapid-acting insulins has been difficult to achieve because to coformulate insulins, interactions between the monomers of each insulin type must be avoided, both before and after injection, to ensure that hybrid hexamers are not formed and the PK profile of each insulin is preserved. IDeg is suitable for coformulation because in the presence of phenol in the pharmaceutical formulation, it takes on the T 3 R 3 conformation (Figure 2). Because only one pole of the hexamer is exposed in this conformation, stable dihexamers are formed, thereby inhibiting any interaction with IAsp. Flexibility in Dosing One of the advantages of IDeg is the increased dosing flexibility associated with its ultralong duration of action. Flexibility in dosing IDeg has been investigated in two open-label randomized treat-to-target phase III trials that compared a flexible dosing regimen of IDeg (IDeg Flex; forced rotating morning and evening dosing to create intervals of 8 40 hours between insulin doses) versus a fixed once/day dosing regimen of either IDeg (IDeg Fixed) or IGlar in people with T2D 41 and T1D 38 (Table 1). In the T1D trial, there was a further 26-week extension in which participants initially randomized to either IDeg dosing regimen could elect to continue to receive IDeg administered at any time during the day (IDeg FreeFlex), providing they maintained a minimum of 8 and a maximum of 40 hours between doses. 38 IDeg, in either the fixed or flexible dosing regimens, was noninferior to IGlar with respect to decreases in A1C (Table 1). 38 However, in subjects with T1D, there were reductions in nocturnal hypoglycemia

10 300 PHARMACOTHERAPY Volume 34, Number 3, 2014 in favor of the flexible dosing schemes versus IDeg Fixed or IGlar. With respect to the lower hypoglycemia rate for IDeg Flex versus IDeg Fixed, it should be noted that there was a higher mean fasting plasma glucose level for the flexible dosing regimen group. This suggests that blood glucose levels may have been somewhat higher during the nocturnal period using the flexible dosing regimen, which may explain the lower rate of nocturnal hypoglycemia. It should be noted that the required irregularity of the flexible dosing schedules was not intended to mimic actual clinical practice and is likely more extreme than would be expected. Nevertheless, these studies demonstrated that changes in injection time of IDeg from day to day did not adversely affect glycemic control or risk of hypoglycemia. Therefore, patients who find it difficult to adhere to the precise timing of injections required for other insulin regimens may find therapy with IDeg more appealing because it can provide greater autonomy with regard to dosing time. This, in turn, could promote improved adherence and thus better glycemic control. The 200 U/ml Formulation Patients who require a high dose of insulin frequently must inject more than once at each administration to deliver the required dose. Therefore, a more concentrated formulation could allow fewer injections for these patients. IDeg has been evaluated in a 200 U/ml formulation (U-200), which allows users to administer up to 160 U (0.8 ml) in a single injection. The PK and PD characteristics of this more concentrated formulation replicate the desirable flat, stable profile demonstrated for IDeg 100 U/ml. 55 In a 26-week randomized phase III trial, glycemic control (A1C reduction) was noninferior to IGlar, and fasting plasma glucose level reduction was significantly greater with IDeg 200 U/ml, with no increased risk of hypoglycemia. 44 Unanswered Questions and Future Studies A number of questions, of course, remain to be answered regarding the use of IDeg in populations or clinical settings not yet studied. The reduced PD variability of IDeg versus IGlar demonstrated in glucose clamp studies has not yet been directly evaluated in clinical practice. Data have not yet been reported for pediatric populations or for inpatient populations where daily titration might be required. However, studies in patients with chronic hepatic 29 or renal 30 disease have shown that these diseases do not result in any unwanted accumulation of IDeg and that IDeg maintains its typical PK profile in these patients, including during dialysis. 30 A dedicated cardiovascular outcomes trial is now underway to establish long-term cardiovascular safety prior to approval in the United States. Similarly, the optimal dose when transferring from other long-acting insulins needs to be determined, including that for patients using their previous insulin twice/day. Although extensively tested in a large clinical development program, no information has yet been reported indicating to what degree the performance reported from randomized clinical trial populations can be achieved in routine clinical practice. The fasting glucose target used in the clinical development program (90 mg/dl) is more ambitious than in some studies and could have affected glucose control as well as the incidence of hypoglycemic events. However, other major trials have used targets within this range. 56, 57 Because people with a history of severe hypoglycemia were excluded from the clinical trial program, it is possible that the reported benefits of IDeg may be even greater in a more representative population of patients. Also, in the reported clinical trials (Table 1), other than in the flexible dosing studies, IDeg was always given with the main evening meal, whereas IGlar could be administered at any time of day according to the label, as long as the time was consistent. For those patients administering IGlar with the morning meal, this could potentially have minimized the difference in reducing nocturnal hypoglycemia. Conclusion Although current basal insulin therapies have been shown to be effective in helping many people with diabetes reach target blood glucose levels, they can be associated with hypoglycemia due to inappropriately peaked or variable action profiles. Also, dosing flexibility is often constrained by an insufficient duration of action producing high peak-to-trough ratios at steady state. IDeg may overcome these limitations; it exhibits flat and stable steady-state PK and PD profiles and possesses a half-life longer than 25 hours with an ultralong duration of action beyond 42 hours. 4, 5 The PK remains stable in

11 INSULIN DEGLUDEC Drab and Philis-Tsimikas 301 patients with chronic hepatic 29 or renal impairment including during dialysis. 30 These characteristics ensure a constancy of effect that results in a lower risk of hypoglycemia than current basal insulin analogs. Individuals who are prone to hypoglycemia, as well as people currently taking basal insulin twice/day, may also find IDeg a more suitable option than their current regimens. Although not currently available in the United States (but approved in Japan, Mexico, and Europe), IDeg could improve the glycemic control to hypoglycemia risk ratio and offer greater flexibility in dosing in patients who find current therapy overly challenging. Although it is clearly not advisable to encourage patients to change daily insulin administration times frequently, it is reassuring that patients can be allowed greater dosing flexibility should it be required due to changes in their daily activities. Additionally, IDeg is the first basal insulin that has been successfully coformulated with a rapidacting insulin. Together, these findings suggest that IDeg has the potential to improve glycemic control, lower the risk of hypoglycemia, and increase the quality of life for a large number of patients with diabetes. Acknowledgments The authors wish to thank Gary Patronek and Gabrielle Parker of Watermeadow Medical for providing writing and editorial assistance. References 1. Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res 2012;29: Owens DR. Insulin preparations with prolonged effect. Diab- Technol Ther 2011;13(Suppl 1):S Heise T, H ovelmann U, Nosek L, Bøttcher SG, Granhall C, Haahr H. Insulin degludec has a two-fold longer half-life and a more consistent pharmacokinetic profile than insulin glargine. Diabetes 2011;60(Suppl 1):11LB[Abstract LB-37]. 20Abstracts_Online.pdf. 4. Heise T, Nosek L, Bøttcher SG, Hastrup H, Haahr H. Ultralong-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab 2012;14: Heise T, Nosek L, Coester H-V, et al. Steady state is reached within two to three days of once-daily administration of ultralong-acting insulin degludec. Diabetes 2012;61(Suppl 1):A259 [Abstract 1013]. 6. Dunn MF. Zinc-ligand interactions modulate assembly and stability of the insulin hexamer a review. Biometals 2005;18: Kaarsholm NC, Ko HC, Dunn MF. Comparison of solution structural flexibility and zinc binding domains for insulin, proinsulin, and miniproinsulin. Biochemistry 1989;28: Kurtzhals P. How to achieve a predictable basal insulin? Diabetes Metab 2005;31(4 Pt 2):4S Simon CR, DeVries JH. The future of basal insulin supplementation. Diabetes Technol Ther 2011;13(Suppl 1):S Heise T, Pieber TR. Towards peakless, reproducible and longacting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies. Diabetes Obes Metab 2007;9: Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 2004;53: Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab 2007;9: Fidler C, Christensen TE, Gillard S. Hypoglycemia: an overview of fear of hypoglycemia, quality-of-life, and impact on costs. J Med Econ 2011;14: Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Factors associated with injection omission/non-adherence in the Global Attitudes of Patients and Physicians in Insulin Therapy study. Diabetes Obes Metab 2012;14: Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study. Diabet Med 2012;29: Havelund S, Plum A, Ribel U, et al. The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res 2004;21: Kurtzhals P, Sch affer L, Sørensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49: Sciacca L, Prisco M, Wu A, Belfiore A, Vigneri R, Baserga R. Signaling differences from the A and B isoforms of the insulin receptor (IR) in 32D cells in the presence or absence of IR substrate-1. Endocrinology 2003;144: Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008;8: Hansen BF, Danielsen GM, Drejer K, et al. Sustained signaling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency. Biochem J 1996;315: Pollak M, Russell-Jones D. Insulin analogues and cancer risk: cause for concern or cause celebre? Int J Clin Pract 2010;64: Currie CJ, Poole CD, Gale EAM. The influence of glucoselowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52: Jonasson JM, Ljung R, Talb ack M, Haglund B, Gudbj ornsdottir S, Steineck G. Insulin glargine use and short-term incidence of malignancies a population-based follow-up study in Sweden. Diabetologia 2009;52: Hemkens LG, Bender R, Grouven U, Sawicki PT. Insulin glargine and cancer. Lancet 2009;374: Colhoun HM, SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009;52: Renehan AG. Insulin analogues and cancer risk: the emergence of second generation studies. Diabetologia 2012;55: ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367: Danne T, Biester T, Blaesig S, et al. Ultra-long pharmacokinetic properties of insulin degludec in adults with type 1 diabetes is preserved in children and adolescents after single-dose administration. Diabetologia 2011;54(Suppl 1):S425 [Abstract 1047-P]. 29. Arold G, Kupcova V, Thrane M, Højbjerre M, Haahr HL. Insulin degludec has similar pharmacokinetic properties in subjects with hepatic impairment when compared to subjects

12 302 PHARMACOTHERAPY Volume 34, Number 3, 2014 with normal hepatic function. Diabetes 2012;61(Suppl 1):A289 [Abstract 1119-P]. 30. Kiss I, Arold G, Bøttcher SG, Thrane M, Haahr HL. Insulin degludec has similar pharmacokinetic properties in subjects with renal impairment and subjects with normal renal function. Diabetes 2012;61(Suppl 1):A296 7 [Abstract 1151-P]. 31. Korsatko S, Deller S, Mader J, et al. Ultra-long pharmacokinetic properties of insulin degludec in younger adults are preserved in geriatric subjects with type 1 diabetes [abstract 1316]. Abstract book of American Association of Clinical Endocrinologists 21st Annual Scientific and Clinical Congress, May 23 27, 2012, Philadelphia, PA, USA /abstracts-and-posters. A Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab 2012;14: Hompesch M, Morrow L, Watkins E, Roepstorff C, Thomsen H, Haahr H. Insulin degludec provides similar pharmacokinetic and pharmacodynamic responses in black, white and Hispanic/Latino subjects with type 2 diabetes. Endocr Rev 2012;33: MON Nosek L, Coester H-V, Thomsen HF, Roepstorff C, Haahr HL, Heise T. Glucose-lowering effect of insulin degludec is independent of subcutaneous injection region [abstract 899P]. Diabetes 2012;61(Suppl 1):A Birkeland KI, Home PD, Wendisch U, et al. Insulin degludec in type 1 diabetes: a randomized controlled trial of a newgeneration ultra-long-acting insulin compared with insulin glargine. Diabetes Care 2011;34: Zinman B, Fulcher G, Rao PV, et al. Insulin degludec, an ultra-long-acting basal insulin, once a day or three times a week versus insulin glargine once a day in patients with type 2 diabetes: a 16-week, randomised, open-label, phase 2 trial. Lancet 2011;377: Heller S, Buse J, Fisher M, et al. Insulin degludec, an ultralong-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, openlabel, treat-to-target non-inferiority trial. Lancet 2012;379: Mathieu C, Hollander P, Miranda-Palma B, et al. on behalf of the NN (BEGIN â : Flex T1) Trial Investigators. Efficacy and safety of insulin degludec in a flexible dosing regimen versus insulin glargine in patients with type 1 diabetes (BEGIN â : Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol Metab 2013;98: Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012; 379: Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care 2012;35: Meneghini L, Atkin SL, Gough SCL, et al. on behalf of the NN (BEGIN â FLEX) Trial Investigators. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in people with type 2 diabetes. Diabetes Care 2013;36: Onishi Y, Iwamoto Y, Yoo SJ, et al. Insulin degludec compared with insulin glargine in insulin-na ıve patients with type 2 diabetes: a 26-week, randomized, controlled, Pan-Asian, treat-to-target trial. J Diab Invest doi: /jdi Philis-Tsimikas A, Del Prato S, Satman I, et al. Effect of insulin degludec versus sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabetic agents. Diabetes Obes Metab 2013;15: Gough SCL, Bhargava A, Jain R, Mersebach H, Rasmussen S, Bergenstal R. Low-volume insulin degludec 200 U/ml oncedaily improves glycemic control similar to insulin glargine with a low risk of hypoglycemia in insulin-na ıve patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN TM LOW VOLUME trial. Diabetes Care 2013;36: Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-J arvinen H. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care 2005;28: Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26: Raskin P, Allen E, Hollander P, et al. INITIATE Study Group. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care 2005;28: Ratner R, Gough SC, Mathieu C, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab 2013;15: Brod M, Christensen T, Bushnell DM. Impact of nocturnal hypoglycemic events on diabetes management, sleep quality, and next-day function: results from a four-country survey. J Med Econ 2012;15: Meneghini LF, Schumm-Draeger P-M, Harris S, Gall MA, Lassota N, Christiansen JS. Local tolerability of insulin degludec is comparable to insulin glargine: a meta-analysis of T1DM and T2DM [abstract 906-P]. Diabetes 2012;61(Suppl 1):A Nishimura E, Sorensen AR, Hansen BF, et al. Insulin degludec, a new generation ultra-long acting basal insulin designed to maintain full metabolic effect while minimising mitogenic potential [abstract 974]. Diabetologia 2010;53(Suppl 1):S Heise T, Tack CJ, Cuddihy R, et al. A new-generation ultralong-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naive people with type 2 diabetes. Diabetes Care 2011;34: Hirsch IB, Bode B, Courreges JP, et al. Insulin degludec/insulin aspart administered once daily at any meal, with insulin aspart at other meals versus a standard basal-bolus regimen in patients with type 1 diabetes: a 26-week, phase 3, randomized, openlabel, treat-to-target trial. Diabetes Care 2012;35: Ma Z, Parkner T, Christiansen JS, Laursen T. IDegAsp: a novel soluble insulin analogs combination. Expert Opin Biol Ther 2012;12: H ovelmann U, Heise T, Nosek L, Bøttcher SG, Hastrup-Nielsen H, Haahr HL. Insulin degludec 200 U/ml is ultra-longacting and has a flat and stable glucose-lowering effect [abstract 912]. Diabetologia 2012;55(Suppl 1):S Blonde L, Merilainen M, Karwe V, Raskin P, TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets the TITRATE study. Diabetes Obes Metab 2009;11: Davies M, Lavalle-Gonzalez F, Storms F, Gomis R, AT.LAN- TUS Study Group. Initiation of insulin glargine therapy in type 2 diabetes subjects suboptimally controlled on oral antidiabetic agents: results from the AT.LANTUS trial. Diabetes Obes Metab 2008;10: