New Long-Acting Basal Insulins: Eberhard Standl and David R

S172 Diabetes Care Volume 39, Supplement 2, August 2016

1 2 INSULIN THERAPY New Long-Acting Basal Insulins: Eberhard Standl and David R. Owen Does BeneﬁtOutweighCost? Diabetes Care 2016;39(Suppl. 2):S172–S179 | DOI: 10.2337/dcS15-3011

Although insulin introduced nearly a century ago has saved the lives of countless people with diabetes, improvements of this therapy continue as significant unmet needs remain (1–4). Even persons with type 2 diabetes who, compared with those with type 1 diabetes, exhibit a much more stable, yet disordered, metabolic milieu only achieve an intended HbA1c target of 7% or lower without hypoglycemic events in a minority of cases (1,3,4). Hypoglycemia and weight gain represent the most important obstacles to achieving the desired glycemic control with insulin therapy, despite major advances in education and empowerment of people with diabetes, the introduction of self-monitoring of blood glucose, improvement in the technical application of insulin, and the availability of a wide array of insulin preparations including insulin analogs (1–4). Intermediate and long-acting basal insulins represent the cornerstone of any insulin therapy regimen, and human NPH insulin, insulin glargine, and insulin detemir are currently the most widely used members of this class of insulin preparations. Discernable progress has been observed with improved day-to-day variability and a lowering in the risk of hypoglycemia with the introduction of the soluble long-acting preparations insulin glargine and insulin detemir compared with NPH insulin, which requires appropriate resuspension prior to administration to reduce variability (5). Against the background of the aforemen- tioned unmet needs, however, a new generation of long-acting basal insulins has emerged aiming at new standards in terms of pharmacokinetics, efficacy, and safety (Fig. 1). Modern drug development occurs in an era of increasingly strict regulations by global institutions such as the U.S. Food and Drug Administration (FDA) and Euro- pean Medicines Agency (EMA) that rightly demand enhanced safety checks of new chemical entities for clinical use such as the new long-acting insulin analogs (6–8). Expensive clinical safety studies are, therefore, required, and cost has thereby become a major issue. This has direct impact on the prescribing of insulins in the emerging economies around the world and even in some developed countries where the cost of NPH insulin has increased. Furthermore, sales of one of the new-generation long-acting insulins, i.e., insulin degludec, have recently been halted by the manufacturer in a country like Germany, as no agreement could be reached with the German authorities over appropriate pricing. Hence, this article seeks to evaluate whether the clinical benefits of the new long-acting insulins in- 1Munich Diabetes Research Group e.V. at the deed justify the cost. Munich Helmholtz Centre, Munich-Neuherberg, Germany 2 Brief Description of Previous and New Long-Acting Basal Insulins Diabetes Research Group, Institute of Life Sci- Figure 2 outlines the chemical structure and modifications derived from the human ences, College of Medicine, Swansea University, Swansea, Wales, U.K. insulin molecule of insulins glargine (Fig. 2A)anddetemir(Fig.2B)aswellasofthe three new long-acting basal insulins discussed in this article (Fig. 2C, D,andE). In Corresponding author: Eberhard Standl, [email protected]. addition, Tables 1 and 2 provide an overview of clinically important time-action This publication is based on the presentations characteristics of current standard long-acting basal insulins and insulin analogs and at the 5th World Congress on Controversies to this new generation of even longer-acting basal insulin analogs, respectively (3). Consensus in Diabetes, Obesity and Hyperten- These, apostrophized by some also as “ultra”-long-acting insulin analogs, clearly sion (CODHy). The Congress and the publication possess a duration of action far beyond 24 h, with a much reduced peak action, of this supplement were made possible in whereas current standard long-acting insulins act for up to 24 h and slightly beyond, part by unrestricted educational grants from AstraZeneca. with higher doses extending to a longer duration of action. However, the new © 2016 by the American Diabetes Association. longer-acting insulins also need to be dosed daily and approximately at the same Readers may use this article as long as the work is time, albeit with some flexibility (see below), as the effect does wane beyond the properly cited, the use is educational and not for 24-h period. profit, and the work is not altered. care.diabetesjournals.org Standl and Owen S173

action profile than insulin detemir but NPH insulin or other options like glucagon- has a discernable peak action 3–4 h after like peptide 1 receptor agonists and rapid- administration while possessing a dura- acting insulin analogs (9). Implementing tion of action of 24 h or more, depending therapy with long-acting insulin ana- on the dose (1,3,4,9–13,15). logs such as glargine or detemir in this In a comparison of the three options context achieved glycemic control similar of standard basal insulins in a “real- to that with NPH insulin or short-acting world” setting, some practically relevant insulin analogs or glucagon-like peptide 1 differences become evident, as can be receptor agonists, although slightly infe- seen in a huge database of 51,964 indi- rior to that with premixed insulins, but viduals with type 1 or type 2 diabetes importantly with the least number of Figure 1—Goals of analog design. hypos, hypoglycemia. exclusively on insulin therapy from 336 side effects, especially hypoglycemia. centers in Germany and Austria. The in- In summary of these and findings In comparison, the duration of action jection frequencies and doses of basal from other comparative studies, the of NPH insulin is considerably shorter, and total insulin per day were lowest following practical, evidence-based being up to 16 h and dose dependent, with the use of insulin glargine, which notions become apparent (1,3,4,9– with a clear peak action after 4–6h typically enables a once-a-day dosing 14,16–18): (1,3,4,9–14). The latter property may regimen, compared with NPH insulin or be responsible for nocturnal hypoglycemia insulin detemir, yet at similar glycemic c Standard long-acting insulin analogs (in- sometime between 2:00 and 4:00 A.M., control and rates of severe hypoglyce- sulin glargine and insulin detemir) are after the administration of NPH insulin at mia (16). A meta-analysis looking into not superior to NPH insulin in efficacy bedtime, or late morning hypoglycemia, data from 9,548 participants with terms as determined by the number of when NPH insulin is given before break- type 2 diabetes failing on oral agents participants reaching HbA1c targets. fast and its peak action not sufficiently from 22 randomized controlled trials c Compared with use of NPH insulin, covered by an appropriate snack. The (RCTs) assessed the comparative effi- the use of the standard long-acting long-acting insulin detemir has a flatter cacy of adding the established long- insulin analogs with relatively flat ac- peak action profile than NPH at low acting insulin analogs to existing oral tion profilesisassociatedwithup doses, but at higher doses a peak action therapies, although without differenti- to a 50% reduced risk of nocturnal is evident 7–14 h after administration ating between insulin detemir and glar- hypoglycemia. (1,3,4,9–13,15). The long-acting insulin gine, compared with adding NPH c All insulin analogs, both short- and glargine has an even smoother peak insulin or premixed insulins containing long-acting insulin analogs, contribute

Figure 2—Chemical structure as derived from the human insulin molecule of long-acting basal insulin analogs. S174 New Long-Acting Basal Insulins Diabetes Care Volume 39, Supplement 2, August 2016

Table 1—Pharmacological profile of current standard basal insulins Basal insulin Insulin classification preparation Onset (h) Peak (h) Duration (h) Variability (CV%) Timing of administration Intermediate acting NPH 1–34–612–16 68 (refs. 1,4) Usually twice daily Long acting Glargine 0.5–2 Flat,somepeak4–12 ;24 32–82 (refs. 1,38,56) Once daily, same time of day Detemir 0.5–2 Flat,somepeak7–14 ;20 27 (refs. 1,4) Once or (often) twice daily CV, coefficient of variation.

to a reduced rate of overall hypoglyce- to more conventional drug therapy, showed a 15–17% reduction in the inten- mia and less weight gain compared mainly based on metformin and/or sul- sively treated subjects (32,33). As to sub- with therapies based on regular human fonylureas, in terms of macrovascular jects with type 1 diabetes, the long-term insulin and NPH insulin. and microvascular outcomes (27). The follow-up of the Diabetes Control and c In contrast to insulin detemir, insulin equivalence in outcomes also included Complications Trial/Epidemiology of Di- glargine typically lowers blood glu- prespecified, detailed cancer outcomes, abetes Interventions and Complica- cose for 24 h, thus allowing for a thus dismissing earlier fears over a tions (DCCT/EDIC) provides comparable once-a-day basal insulin regimen in higher cancer risk related to the use of evidence (34,35). So, insulin therapy most patients. Insulin glargine is insulin glargine (27). Furthermore, some clearly is a major contributor to the suc- currently regarded as the “gold suggestive evidence in favor of insulin cessful reduction of long-term diabetes standard” basal insulin (19), i.e., ex- glargine was generated from the complications in both type 1 and type 2 cluding regimes using insulin infu- ORIGIN-GRACE substudy in reducing diabetes. sion devices. the progression of carotid-intima thick- The new generation of long-acting in- c Hence, all representatives of the new ening, i.e., a surrogate of CV risk (28), sulin analogs seeks to further improve generation of ultra-long-acting insu- and in a national administrative claims on many features of an ideal basal in- lins, i.e., insulins degludec, pegylated database for acute myocardial infarc- sulin, which includes not only a duration lispro (PegLispro), and glargine U300, tion (28). of action beyond 24 h without possess- have mostly been evaluated in head- The mega-trials UK Prospective Dia- ing an action peak but also a lower intra- to-head comparisons in RCTs against betes Study (UKPDS), Action in Diabetes individual and interindividual day-to-day insulin glargine as the reference stan- and Vascular Disease: Preterax and variability of action (the assessment of dard (14,15,20–26). Diamicron MR Controlled Evaluation which, however, has sometimes yielded (ADVANCE), and Veterans Affairs Diabe- rather variable results [Tables 1 and 2]), Whether the benefits of long-acting tes Trial (VADT), although not specifically along with a minimal risk for inducing hy- insulin analogs translate long-term studying a particular long-acting insulin poglycemia and incurring weight gain. into a reduction in micro/macrovascular but, rather, seeking to intensify glycemic Clearly, such attributes should result in diabetes complications is a largely unad- control by the use of multiple drugs in- an overall improvement in quality of life dressed issue, as only very few RCTs cluding insulin in a randomized, con- and increased patient compliance with have been of long enough duration trolled fashion, have recently provided treatment requirements. and include sufficient numbers of partic- evidence from open follow-up observa- Insulin degludec is a second-generation ipants for a meaningful evaluation of tions after the initial RCT that the ear- acylated insulin following insulin detemir this important aspect. One such trial is lier intensive glycemic control was (Fig. 2), again a soluble insulin formula- the Outcome Reduction With Initial ultimately effective in reducing long- tion, which upon injection into the subcu- Glargine Intervention (ORIGIN) trial, term CV events by some 17% and, in taneous tissue forms multihexamer which looked into cardiovascular (CV) the UKPDS, also in reducing overall mor- chains. The latter serves as a depot prior outcomes over a 6-year period in tality to a similar extent (29–31). A meta- to degradation into dimers and mono- 12,612 persons (predominantly persons analysis of these and other studies, mers, which are then absorbed into the with early type 2 diabetes and some looking selectively and post hoc at circulation (36). Degludec has a low af- [12%] with impaired glucose toler- nonfatal myocardial infarction during finity for the human IGF-1 receptor, ance). Glargine therapy was similar theRCTphaseofthesetrials,also comparable with human insulin, with a

Table 2—Pharmacological proﬁle of new ultra-long-acting basal insulins (>24 h) Insulin Within-subject preparation Onset (h) Peak (h) Duration(h) variability (CV%) Timing of administration T1/2 (h) Steady state (days) Degludec ND Flat, no peak .24 20 (refs. 38,39) Once daily, any time of day (?) 25* 4.2 Glargine U300 ND Flat, no peak .24 17–35 (in T1D) (ref. 42) Once daily 63 h 18 3–4 PegLispro ND Flat, no peak .24 ,18 (ref. 56) Once daily 39* 6.6 CV, coefﬁcient of variation; ND, not determined due to the methodologic approach used; T1/2, half-life time; T1D, type 1 diabetes. *Methodologic limitation, since the insulin assay detects only total, not free, insulin concentration. care.diabetesjournals.org Standl and Owen S175

low mitogenic-metabolic potency ra- diabetes (22,25,26), demonstrate and is well recognized as a major barrier tio (37). It has a half-life of 25 h, which noninferiority to insulin glargine to achieving the required glycemic con- seems to be almost twice as long as U100, although at a slightly higher trol in the majority of insulin-requiring glargine, with a lower degree of vari- dose requirement of ;10–18%, but persons with diabetes (1). Insulin degludec ability in its glucose-lowering effect with a 25% reduced risk of nocturnal has been clearly demonstrated to be over 24 h when at steady state (38,39) hypoglycemia over a 6-month period, equivalent to insulin glargine in lower- (although those measurements have already evident during the titration ing HbA1c in key RCTs in both type 1 and some methodologic limitations). An ex- period (43). In addition, there was type 2 diabetes (14,23,24). However, tensive clinical development program negligible weight gain with the new the risk of hypoglycemia, especially with degludec in both type 1 and high-strength glargine regardless of nocturnal hypoglycemia, was further type 2 diabetes has demonstrated age, BMI, and diabetes duration (44). reduced by ;25% during the mainte- noninferiority to glargine in terms of ef- Glargine U300 has recently been ap- nance period of the trials despite ficacy with a reduced risk of nocturnal proved in the U.S. and several coun- somewhat lower fasting plasma glu- hypoglycemia (1,3,4,10,13,14,23,24,38,40). tries in Europe. cose concentrations (40). In addition, To date, insulin degludec has been ap- PegLispro (LY2605541), at this mo- insulin degludec allows a more flexible proved for use in Europe (including its ment an investigational insulin only, approach to the timing of insulin ad- use in children), Asia, and Latin America is a long-acting insulin that comprises ministration to better accommodate and very recently also in the U.S. (Sep- insulin lispro covalently bound, via a the recipients’ ever-changing daily life tember 2015), based on additional urethane bond at lysine B28, to a pattern (1,3,4,10,13,50,54). Such im- interim data from a CV outcome study 20-kDa polyethylene glycol (PEG) chain proved convenience seems to result (A Trial Comparing Cardiovascular (Fig. 2), thereby increasing the hydrody- in better compliance with therapy Safety of Insulin Degludec Versus Insu- namic size of the insulin-PEG complex and an enhancement in the patients’ lin Glargine in Subjects With Type 2 Di- (1,3,4,15,20,21,45–48). PegLispro has quality of life (50,54). Finally, the use abetes at High Risk of Cardiovascular an even lower binding affinity for both of insulin degludec has been found to Events [DEVOTE], clinical trial reg. no. the insulin receptor and IGF-1 receptor be associated with a 10% lower dose NCT01959529, clinicaltrials.gov). This than lispro and a lower mitogenic po- requirement compared with both in- requirement was deemed necessary tency than human insulin (45,47,48). It sulin detemir and insulin glargine in a based on the original phase 3 trials, possesses a prolonged duration of action meta-analysis of available RCTs (55). which suggested the presence of an en- exceeding 36 h as a result of delayed This seems particularly noteworthy, as hanced CV risk with insulin degludec in absorption and reduced clearance, the use of insulin glargine yields the comparison with insulin glargine, al- with a low intrasubject variability in glu- lowest insulin doses among the current though this interpretation was not uni- cose lowering and a lower and quite standard long-acting insulins (16). versal. The findings from the DEVOTE different tissue distribution compared Insulin glargine U300 also provides a study in 7,500 high-risk individuals with the other insulin preparations flatter and more reproducible pharma- with type 2 diabetes will be invaluable (45,47,48). Both animal and human cokinetic profile resulting in a more even owing to its prospective, double-blind studies suggested that PegLispro may daylong blood glucose–lowering action design. have a preferential hepato-specificac- than its predecessor (insulin glargine Glargine U300 is a new higher- tion on glucose metabolism compared U100) (1,3,4,22,25,26,41) (Table 2). The strength formulation of insulin glargine with insulin glargine (49). Early phase 3 intraindividual variability measures were at 300 IU/mL rather than the usual glargine clinical studies (IMAGINE) include eight low and ranged from 17 to 35% (42). at 100 IU/mL, which alters its pharmacoki- pivotal studies, three of which are double- Head-to head comparisons of glargine netic and pharmacodynamic properties blind, and most involve glargine (U100) as U300 and standard glargine U100 in (1,3,4,22,25,26,41,42). Glargine U300 the comparator. These have demon- RCTs showed identical efficacy in terms forms a more compact subcutaneous de- strated that PegLispro was consistently of lowering HbA1c, although at a slightly pot with its surface area reduced by half superior under these conditions to glargine higher dose requirement of ;10–18%. ; and its volume by two-thirds (Fig. 2), in terms of lowering HbA1c andincausing An 25% decrease of nighttime con- resulting in a retarded and prolonged less nocturnal hypoglycemia with a reduc- firmed or severe hypoglycemia, how- dissolution from the subcutaneous tis- tion of ;40% (20,21,50–52). However, an ever, and only minimal weight gain sue compared with generally available increase in liver enzyme levels (alanine were observed with the use of insulin standard glargine (U100) (Tables 1 and 2). aminotransferase) with an increase in liver glargine U300 in studies looking at sub- Also, its metabolic degradation to the me- fat content has been noted, although no jects with type 2 diabetes (22,25,26,43). tabolites M1 (GlyA21 insulin) and M2 acute, severe, hepatocellular drug-induced Due to the longer duration of action, in- (GlyA21, des-ThrB30) is similar to that of liver injury has been observed to date with sulin glargine U300 has been shown to insulin glargine U100 (42). These metabo- PegLisproinstudiesupto78weeks provide some increased flexibility in the lites show binding characteristics to the (20,21,51,53). timing of the insulin injection of approx- insulin receptor and IGF-1 receptor imately 63 h (58,59). Quality-of-life comparable with human insulin. A Arguments in Favor of the New assessments have shown a slight im- number of key phase 3 randomized Insulins provement with the use of glargine parallel-group studies (EDITION), pre- Hypoglycemia is a most feared and U300 over insulin glargine U100 dominantly in persons with type 2 costly complication of insulin therapy (1,3,4,22,25,26). In addition, the new S176 New Long-Acting Basal Insulins Diabetes Care Volume 39, Supplement 2, August 2016

high-strength glargine seems to have especially nocturnal hypoglycemia, by commenced in November 2013, designed the substantial weight of indirect ;25% compared with insulin glargine, as a double-blind study comparing insulin safety evidence, both CV and carcino- the FDA in its assessment highlighted degludec with insulin glargine involving genesis, emanating from the ORIGIN the fact that this benefit was not a con- ;7,500 subjects with type 2 diabetes at trial (27). sistent feature seen across the different high CV risk (6–8). Obviously, the FDA set The experimental PegLispro long- types of diabetes or definitions of hy- safety margins for marketing approval acting insulin analog also yields a rela- poglycemia, in particular the more with an upper bound of the 95% CI tively flat and peakless pharmacokinetic objective definitions of hypoglycemia ,1.8 have now been met, but it remains profile along with a more reproducible (14,23,24,40,54,55,57). Also, interpreting to be seen whether the full outcome re- glycemic action profile compared with the relative safety of these two basal in- sults of the ongoing trial, once available, insulin glargine U100 and a much ex- sulins during a set period overnight will ultimately demonstrate CV safety as tended duration of action, exceeding (0000–0559 h) is difficult owing to the required for permanent approval. De- 36 h, reaching steady state within 7–10 differences in their pharmacokinetic spite these uncertainties and its some- days (48) (Table 2). Based primarily on profiles and the assumption about the what controversial benefits in reducing animal studies, PegLispro is catabolized timing of administration of the main nocturnal hypoglycemia, the cost associ- to smaller peptides and/or amino acids comparator insulin glargine, com- ated with the use of insulin degludec in and to lysine-PEG, the latter being elim- pounded by the inadequacy of data cap- countries where it is or, rather, has been inated via biliary and renal routes ture during this nighttime period. available is substantially higher than with (1,3,4,45). There is also a lesser variabil- Extending the overnight period by 2 h any other basal insulin, e.g., some 50–70% ity in glucose lowering with PegLispro negated the difference in the nocturnal higher than insulin glargine or detemir compared with insulin glargine (56) ac- hypoglycemic event rate between insu- and several-fold higher than NPH insulin companied by less weight gain and fewer lin degludec and glargine for both indi- in countries like Germany, Denmark, or nocturnal hypoglycemic episodes in viduals with type 1 diabetes and with the U.K. In fact, the manufacturer has de- early phase 2 studies with PegLispro in type 2 diabetes. The perceived safety cidedtostopmarketingthedrugin both type 1 (51) and type 2 diabetes benefit did not translate into an efficacy Germany, since no agreement could (21,50,56). Its preferential hepatic (inhi- advantage either. be reached with the authorities over bition of glucose production) versus The FDA has been able to approve the the appropriate pricing. Also, in other peripheral (glucose disposal) activity drug for the U.S. only recently (Septem- countries, the benefit-to-cost ratio has makes it perhaps more similar to endog- ber 2015), based on additional interim been challenged, and discussions on enous insulin when compared with data obtained from the FDA-mandated this issue are bound to continue, espe- other exogenously administered in- specific CV outcome trial (DEVOTE), in cially since insulin glargine U300, with sulins that possess a predominant ef- line with the guidance put forward by pharmacokinetic/pharmakodynamic fect on peripheral glucose disposal this agency in 2008 for approval of properties not too dissimilar to those (1,3,4,15,20,21,49). In a series of phase new blood glucose medications (5). Ap- of insulin degludec, has become avail- 3 studies (IMAGINE), it shows a consis- proval requires a hazard ratio (HR) with able at a cost comparable with that of tent, although marginal, but statisti- an upper bound of the 95% CI ,1.3 for previous insulin glargine U100. cally greater HbA1c-lowering capacity major adverse cardiovascular events The new high-strength long-acting (0.2–0.3% HbA1c) than glargine U100 (MACE) (composite of CV death, nonfa- formulation of insulin glargine U300 in- in persons with either type 1 or type 2 tal myocardial infarction, and nonfatal herits the indirect proof of long-term diabetes on intensified insulin therapy stroke) from RCTs during phase 2/3 CV and cancer safety based on the ORIGIN or persons with type 2 diabetes on of drug development, whereas .1.8 trial involving insulin glargine U100 basal insulin in addition to oral therapy necessitates a preapproval CV outcome strength conducted over a period of (20,51,52). A significant lower rate of trial and a value in between requires a ;6 years (27). In RCTs (EDITION), glargine nocturnal hypoglycemia in the range of postapproval CV trial. At the time of the U300 was seen to be noninferior, though 36–45% has been observed compared first FDA assessment in 2012, there were not superior, to standard glargine U100 with that in those taking insulin glargine 132 case subjects with CV events avail- (22,25,26,43,58). There was, however, a U100 (1,3,4,15,20,21,50–52). There was able (MACE+, i.e., plus unstable angina) reduction of ;25% in confirmed noctur- also some weight loss associated with in .7,716 patient-years of exposure nal hypoglycemia (#70 mg/mL) or se- the use of PegLispro in contrast to some with an HR of 1.30 (95% CI 0.88–1.93), vere hypoglycemia over a 6-month weight gain with insulin glargine, amount- thus exceeding the 1.8 limit (4). Addi- study period with the difference already ing to an absolute difference of ;2kg tional analysis based on MACE, i.e., ex- evident during a titration period and con- (20,45,50,51), but warranting a closer cluding unstable angina, involved 91 tinuing thereafter (22,25,26,43). With the look into whether the efficacy of this new case subjects with CV events resulting period of overnight observation extended insulin at peripheral tissues is adequate. in a higher risk with an HR of 1.67 from midnight to 8:00 A.M., the differ- (1.01–2.75). As a consequence, the ence was 16%, confirming a clinically Arguments Challenging the Benefitof above-mentioned specificCVoutcome relevant benefit of glargine U300 the New Long-Acting Insulins trial was mandated by the FDA, as op- compared with glargine U100 (59). Whereas the initial studies with insulin posed to a less strict stance of the EMA, Conversely, the reduction of overall hy- degludec seemed to demonstrate a re- Japanese, and other authorities that poglycemia was much less impressive, ductioninepisodes of hypoglycemia, have approved the drug. DEVOTE was at ;10% at any time of the day, care.diabetesjournals.org Standl and Owen S177

pointing to some potential problems consistently observed increase of liver and insufficient peripheral action will during daytime. Indeed, in a meta-analysis transaminases (still remaining within the be required for PegLispro, whereas insu- of the phase 3 clinical trials on glar- normal range) (20,21,53,60). The observed lin glargine U300 has the benefitofthe gine U300, the highest prevalence of increase in liver fat by MRI also requires long-term ORIGIN study. hypoglycemia was seen between 6:00 a sound assessment before the overall The cost associated with use of insulin and 10:00 A.M. when insulin glargine benefit-to-risk ratio of this new ultra-long- degludec in countries where it has become was dosed at bedtime (43,59). As for in- acting insulin can be determined (53). available is substantially higher than with sulin degludec, the lower risk of hypogly- any other basal insulin, e.g., some 50–70% cemia did not translate to improved Consensus and Conclusions higher compared with insulins glargine or glycemic control despite the 9–18% Hypoglycemia remains a major obsta- detemir and several-fold higher than NPH higher daily dose required in the case of cle in our ability to achieve the re- insulin, which has generated considerable insulin glargine U300, which was accompa- quired glycemic target in the majority debate. In fact, insulin degludec has been nied by a minimal increase in weight (43). of our patients. The introduction of in- withdrawn from marketing in Germany by Both the FDA and EMA have approved insulin glargine and insulin detemir, both the manufacturer owing to the inability to sulin glargine U300 for clinical use in 2015. soluble insulin preparations with a come to an agreement on the pricing. Fur- Per-unit cost for glargine U100 and glar- more protracted action up to 24 h, thermore, insulin glargine U300, with prop- gine U300 should be comparable and in- smoother time-action profile, and re- erties similar to those of insulin degludec, deed are in countries like the U.S. or U.K. In duced peak action, has resulted in no- has meanwhile become available in view of the higher daily dose requirement table improvement and a significant many countries at a cost comparable in the clinical trials, one might, however, reduction in the risk of hypoglycemia with that of previous insulin glargine argue that the price should be discounted compared with NPH insulin, especially U100. As investigational insulin PegLispro by 10–20%forglargineU300tobetterre- during nighttime. is currently being evaluated in a large flect equivalency. The recently available new long-acting phase 3 clinical trial program before a la- Despite extensive basic and early basal insulin analogs insulin degludec, the beling package can be submitted to the clinical research leading to a portfolio more concentrated insulin glargine U300, regulatory authorities, a final assessment of well-designed double-blind studies, and PegLispro (the latter an investiga- of its cost–to–clinical benefitratio insulin PegLispro is still at a relatively tional drug only) all demonstrate superior seems premature. Meanwhile, Lilly has early phase of development, and the pharmacokinetic and pharmacodynamic stopped the insulin PegLispro develop- dossier for submission to the regulators properties with an even more protracted ment program as a result of internal seems to be delayed. PegLispro achieves action, i.e., .24 h, with a much lower peak discussions (61). a statistically significantly greater im- action profile compared with currently provement in glycemic control than available basal insulin preparations. insulin glargine, and the risk of noctur- The main clinical advantage of these Duality of Interest. E.S. has received lectur- nal hypoglycemia is reduced by nearly new long-acting basal insulins is the ing honoraria and consultation fees from half compared with insulin glargine substantial reduction in nocturnal hypo- AstraZeneca, Bayer, Boehringer Ingelheim, (1,3,4,15,20,21,43,51). However, day- glycemia, although this is somewhat con- Merck-Serono, Merck Sharp & Dohme/Merck, fi time hypoglycemic events were signifi- troversial in the case of insulin degludec. Novartis, and Sano . D.R.O. has received honoraria from Boehringer Ingelheim, Eli Lilly, cantly increased, possibly due to its Other benefits include flexibility of Novo Nordisk, Roche, and Sanofi for lectures hepato-preferential action resulting timing of insulin administration, the and involvement in advisory boards. No other in a greater inhibition of hepatic glucose lack of weight gain or even weight loss, potential conflicts of interest relevant to this output postprandially (20,49). It remains and some improvement in quality-of-life articlewerereported. to be seen whether a reduction in the aspects. References dose of short-acting insulin or other hy- For the time being, the use of the 1. Cahn A, Miccoli R, Dardano A, Del Prato S. poglycemic agents may abolish this un- longer-acting insulin glargine U300 New forms of insulin and insulin therapies for toward daytime hypoglycemia risk. This seems to present the least issues; it ap- the treatment of type 2 diabetes. Lancet Diabe- adaptation may, however, result in a pears to offer advantages comparable tes Endocrinol 2015;3:638–652 loss of superiority in terms of efficacy with those of the other new long-acting 2. DeFronzo RA, Ferrannini E, Zimmet P, Alberti compared with standard insulin glargine basal insulins, yet at a price similar to that KGMM, Eds. International Textbook of Diabetes fi fi Mellitus. 4th ed. John Wiley and Sons, Sussex, and perhaps unmask an insuf cient ef - for insulin glargine U100. The higher daily England, 2015, p. 3–1224 cacy at peripheral muscle and adipose tis- dose requirement seen in the clinical drug 3. Owens DR, Matfin G, Monnier L. Basal insulin sues, as might be evidenced by increased development program might even war- analogues in the management of diabetes mel- lipolysis and some loss of body weight rant a 10–20% discount. litus: What progress have we made? Diabetes – (19,50,51,57). This aspect clearly needs Based on additional interim safety Metab Res Rev 2014;30:104 119 4. Owens DR, Rosenstock J. New forms of in- more evaluation, especially since 1 unit data from an ongoing mandated CV out- sulin analogs in development: the quest for a of insulin PegLispro contains 9 nmol insulin come trial (DEVOTE), insulin degludec better basal insulin. In Therapy for Diabetes in contrast to 6 nmol in insulins degludec has recently been approved for market- Mellitus and Related Disorders. 6th ed. Umpierrez or glargine U300. The observed increase in ingalsointheU.S.,asinmanyother GE, Ed. Alexandria, VA, American Diabetes As- sociation, 2014, p. 480–507 triglyceride concentrations needs to be countries in Europe and Asia before. 5. Lucidi P, Porcellati F, Marinelli Andreoli A, explained and possible consequences An even more rigorous safety assess- et al. Pharmacokinetics and Pharmacokinetics need to be explored as well as the very ment including potential liver toxicity and pharmacodynamics of NPH insulin in S178 New Long-Acting Basal Insulins Diabetes Care Volume 39, Supplement 2, August 2016

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