Author proof done. Insulin degludec. Vishakha V. Jain, Omprakash Gupta

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1 Review Article Author proof done Insulin degludec Vishakha V. Jain, Omprakash Gupta Abstract Insulin analogues have revolutionized the treatment of diabetes mellitus, and the advent of newer insulin analogues have provided better glycemic control with lesser incidence of hypoglycemia. Insulin degludec is a second-generation, ultra-long-acting acylated basal insulin analogue that possesses a flat, stable glucose-lowering effect in patients with type 1 or type 2 diabetes mellitus. Findings from clinical trials have demonstrated that newgeneration, once-daily basal insulin degludec provides similar A1C control as compared to insulin glargine, both administered as basal-oral therapy or in combination with insulin aspart, with the added benefits of lower rates of hypoglycemia, particularly nocturnal hypoglycemia. Keywords: Basal insulin, insulin analogues, insulin degludec Introduction Insulin analogs have changed the way diabetes has been managed in the past and opened vistas of artificially modified insulin molecules, which mimic the endogenous insulin in a much better way and offer better metabolic control. Insulin analogues provide better glycemic control while reducing the risk of hypoglycemia, especially nocturnal hypoglycemia. Long-acting insulin analogues (glargine and detemir) provide an optimal basal insulin level and decrease the incidence of hypoglycemia. [1] The perfect basal insulin product can be injected into subcutaneous tissue without causing irritation, release insulin continuously at a constant rate for at least 24 h, be stable, not contribute to weight gain, have a low risk of allergic reactions, and, very importantly, minimize the risk of hypoglycemia. Quick Response Code: Access this article online Website: DOI: / Both of the first-generation basal insulin analogues presently available have suboptimal pharmacokinetic (PK) properties and do not have the peakless pharmacodynamics (PD) effect enduring over 24 h after single daily dose. [2] Current products either operate through isoelectric precipitation (insulin glargine; IGlar) or employ an albumin-binding acyl tether (insulin detemir). But, recently, there has been much research going on about second-generation insulin analogues in an effort to obtain ideal 24-h PD profile. Such few molecules are insulin degludec (IDeg; extensive subcutaneous supramolecular assembly coupled to a large-scale allosteric reorganization of the insulin hexamer) and LY (coupling to polyethylene glycol to delay absorption and clearance). [2] These second-generation analogues overcome the disadvantages of firstgeneration insulin analogues. [3] This paper reviews the basic and clinical studies performed on degludec so far and highlights the possible role this molecule can play in the management of diabetes mellitus. Insulin Degludec IDeg is an ultra-long-acting acylated basal insulin Department of Medicine, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, Maharashtra, India Address for correspondence: Dr. Vishakha V. Jain, Department of Medicine, Mahatma Gandhi Institute of Medical Sciences, Sewagram, Wardha , Maharashtra, India. drwish1079@rediffmail.com September 2013 Vol 18 Issue 2 Journal of Mahatma Gandhi Institute of Medical Sciences

2 104 Table 1: Comparison of various insulin [6] Basal insulin Onset Peak Duration NPH 1-2 h 4-8 h 8-12 h Glargine min No peak h Detemir min No peak h Degludec min No peak Over 24 h analogue that possesses a flat, stable glucose-lowering effect in patients with type 1 or type 2 diabetes mellitus. [4] IDeg achieves these PK properties by forming soluble multi-hexamers upon subcutaneous injection, resulting in the formation of a depot in the subcutaneous tissue, which is slowly released and absorbed into circulation, giving it a very long duration of action with a half life exceeding 25 h [5] and a consistent glucose-lowering effect of 42 h at steady state. Table 1 compares the onset and duration of action of various insulins. IDeg has been associated with slightly less weight gain and fewer nocturnal hypoglycemic episodes when compared with IGlar in some, but not all, clinical studies. [7,8] Insulin receptorbinding kinetics of IDeg is similar to that of human insulin (HI). In albumin-free conditions, the affinity of IDeg for both HI receptor isoforms (HIR-A and -B) is similar (13% and 15% relative to HI), while the affinity for human IGF-1 receptor is lower (2% relative to HI). [3] Pharmacodynamics and Pharmacokinetics of Insulin Degludec A study involving 12 type 1 diabetic subjects showed that IDeg had a half life longer than 24 h and was found to be detectable in the circulation for at least 96 h after injection; however, it is not known whether or not it is still biologically active at that time. Steady state concentration of IDeg is achieved within 3 days of once-daily dosing. Total exposure during one 24-h dosing interval and maximum concentration of IDeg at steady state increased proportionally with increasing dose. The steady state PK and pharmacodynamic profiles of IDeg were relatively peakless and evenly distributed over a 24-h dosing interval. Insulin receptor binding studies and in vitro studies have indicated that IDeg is comparable to HI in its low affinity for the HI-like growth factor-1 receptor, with a similar low mitogenic/metabolic potency ratio and, therefore, no proof of carcinogenicity. [9] A randomized, double-blind, parallel-group study was carried out to compare the PD variability of Jain and Gupta: Insulin degludec IDeg with that of IGlar under steady state conditions. Fifty-four patients with type 1 diabetes and a mean glycosylated hemoglobin (HbA1c) of 7.7 ± 0.9% were treated with 0.4 U/kg of IDeg or glargine, once daily for 12 days. Euglycemic glucose clamp was performed for 24 h, and the within-subject variability was estimated on log-transformed PD end-points derived from glucose infusion rate profiles that were noted during clamp studies. IDeg was associated with significantly lesser PD variability than glargine on all protocol PD variability parameters, including total metabolic effect (P < ). IDeg s metabolic effect was exactly evenly distributed between the first and the second 12 h, and this distribution was less variable than with glargine (P < 0.001). Thus, it was concluded that IDeg administered once daily was significantly less variable and more stable in maintaining euglycemia as compared to glargine. [10] Use of Insulin Degludec There have been many phase 2 and phase 3 clinical trials with IDeg in patients with type 1 diabetes mellitus as well as type 2 diabetes mellitus. Here, we have discussed some of these clinical trials to understand the utility of IDeg. Type 1 diabetes mellitus In a 16-week, randomized, open-label trial, participants received subcutaneous injections of IDeg in two different doses: Group A received 600 μmol/l (n = 59), group B received 900 μmol/l (n = 60), and group C received IGlar (n = 59), all given once daily in the evening. Insulin aspart was administered at meal times. At 16 weeks, mean A1C was comparable for group A (7.8 ± 0.8%), group B (8.0 ± 1.0%), and group C (7.6 ± 0.8%), as was the fasting plasma glucose (PG; 8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/l, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for group A as compared with that for group C [rate ratio (RR): 0.72 (95% CI )] and 10% lower for group B as compared with that for group C [RR: 0.90 ( )]; rates of nocturnal hypoglycemia were 58% lower for group A [RR: 0.42 ( )] and 29% lower for group B [RR: 0.71 ( )]. Mean total daily insulin dose was similar to that at baseline. Therefore, this clinical trial concluded that, in patients with type 1 diabetes mellitus, IDeg is safe and well-tolerated and provides comparable glycemic control to IGlar at similar doses with reduced rates of hypoglycemia. [11] Another study showed that the rates of overall and nocturnal hypoglycemia of IDeg and IGlar Journal of Mahatma Gandhi Institute of Medical Sciences September 2013 Vol 18 Issue 2

3 Jain and Gupta: Insulin degludec 105 and the risk reductions as compared with glargine were 47.9 and 66.2 events/patient-year (relative risk 0.72) and 5.1 and 12.3 events/patient-year (relative risk 0.42), both in the favor of IDeg once daily. [12] Therefore, in patients with type 1 diabetes mellitus, IDeg was comparable to the present basal insulin, and it was safe with decreased rates of hypoglycemia and nocturnal hypoglycemia. Type 2 diabetes mellitus A study among diabetes type 2, patients tested IDeg in either a once daily regimen or a thrice weekly regimen as compared to that against IGlar. All efficacy outcome measures, including the mean weekly insulin dose, were similar as compared with each other and with IGlar. This study among type 2 diabetes patients found no significant differences in the rate of confirmed hypoglycemic events among degludec once daily, degludec thrice weekly, and IGlar once daily. Although hypoglycemic events occurred less with degludec once daily, they occurred more in the degludec thrice weekly treatment group. [13] In another 16-week, open-label, randomized, treat-totarget trial insulin-naive subjects with type 2 diabetes (18-75 years) and a HbA1c of 7-11% were randomized to twice-daily IDeg-aspart (IDegAsp) (n = 61), alternative formulation (AF) (n = 59), or biphasic insulin aspart 30/70 (BIAsp 30) (n = 62), all in combination with metformin. Insulin was administered before breakfast and before dinner (main evening meal) and titrated to before breakfast and before dinner PG targets of mmol/l. Mean HbA1c after 16 weeks was comparable for IDegAsp, AF, and BIAsp 30 (6.7, 6.6, and 6.7%, respectively). With IDegAsp, 67% of subjects achieved HbA1c <7.0% without confirmed hypoglycemia in the last 4 weeks of treatment as compared with 53% AF and 40% BIAsp 30. Mean fasting PG was significantly lower for IDegAsp vs. BIAsp 30 [treatment difference (TD): 0.99 mmol/l (95% confidence interval: 1.68; 0.29)] and AF vs. BIAsp 30 [TD: 0.88 mmol/l ( 1.58; 0.18)]. A significant 58% lower rate of confirmed hypoglycemia was found for IDegAsp vs. BIAsp 30 [RR: 0.42 (0.23; 0.75)]; rates were similar for AF vs. BIAsp 30 [RR: 0.92 (0.54; 1.57)]. IDegAsp and AF had numerically lower rates of nocturnal as confirmed hypoglycemia vs. BIAsp 30 [RR: 0.33 (0.09; 1.14) and 0.66 (0.22; 1.93) respectively]. It was concluded that IDeg provided comparable overall glycaemic control to BIAsp 30 with a significantly lower rate of hypoglycemia. [14] Another similar 16-week, open-label trial comparing the safety and efficacy of IDegAsp, an AF (55% IDeg and 45% IAsp), and IGlar in insulin-naïve subjects with type 2 diabetes inadequately controlled with oral antidiabetic drugs; subjects were randomized to oncedaily IDegAsp (n = 59), AF (n = 59), or IGlar (n = 60), all in combination with metformin. After 16 weeks, mean A1C decreased in all groups to comparable levels (IDegAsp: 7.0%; AF: 7.2%; IGlar: 7.1%). Mean 2-h post dinner PG increase was lower for IDegAsp (0.13 mmol/l) and AF (0.24 mmol/l) than for IGlar (1.63 mmol/l), whereas mean FPG was similar (IDegAsp: 6.8 mmol/l; AF: 7.4 mmol/l; IGlar: 7.0 mmol/l). It was concluded that once-daily IDegAsp was safe, well tolerated, and provided comparable overall glycemic control to IGlar at similar low rates of hypoglycemia, but better post-dinner PG control. [15] In another phase 2 study comparing IDeg either once daily or thrice weekly or IGlar once daily, all in combination with metformin. At conclusion, mean HbA1 C levels were similar in all treatment groups, at 7.3% (SD 1.1), 7.4% (1.0), 7.5% (1.1), and 7.2% (SD 0.9), respectively. The incidence of hypoglycemia and adverse events was similar across all groups, with no apparent treatment-specific pattern. This study demonstrated that IDeg provides comparable glycemic control to IGlar without additional adverse events and might reduce the dosing frequency due to its ultra-long action profile. This holds better potential for better patient compliance and tolerability, while maintaining safety and efficacy. [15,16] Therefore, in patients with type 2 diabetes mellitus, IDeg provides comparable efficacy in terms of glycemic control with decreased rates of hypoglycemia. Safety and Efficacy In a study evaluating the safety and efficacy of IDeg in either insulin-naïve patients or on patients on antidiabetic drugs, participants were randomized to 1) once-daily IDeg in a prespecified-dosing schedule, creating 8-40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily IGlar at the same time each day (IGlar OD; n = 230). After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA(1c) by 1.28, 1.07, and 1.26% points, respectively [estimated TD (IDeg OD Flex-IGlar OD): 0.04% points ( 0.12 to 0.20), confirming non inferiority]. No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates September 2013 Vol 18 Issue 2 Journal of Mahatma Gandhi Institute of Medical Sciences

4 106 of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. The use of extreme dosing intervals of 8-40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety. [7] In studies involving the binding affinity of IDeg to IGF-1 receptors, the affinity of IDeg for the human IGF-1 receptor was found to be low, with a molecular safety that is similar to HI. This allows omitting of any proof of carcinogenicity with IDeg in comparison to concerns regarding possible metabolic and mitogenic potencies of IGlar. [17] In a systematic review and meta-analysis, pooled patient-level data for self-reported hypoglycemia from seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs. IGlar OD were analyzed. A total of 4330 subjects (2899 IDeg OD vs IGlar OD) were analyzed. Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed, and severe hypoglycemic episodes were reported with IDeg vs. IGlar: Estimated RR: 0.83[0.70; 0.98](95% CI), RR: 0.64[0.48; 0.86] (95% CI), and RR: 0.14[0.03; 0.70](95% CI). In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar (RR:0.83[0.74; 0.94](95% CI) and RR: 0.68[0.57; 0.82](95% CI)). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR: 0.75[0.60; 0.94] (95% CI)). Reduction in hypoglycemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes. [18] In another metaanalysis, it has been found that, as compared to IGlar, IDeg also improves both physical and mental status of patients with type 2 diabetes mellitus. [19] Flexibility of Dosing Time Optimal glycemic benefits are achieved with the injection of basal insulin at a consistent time every day. But, there are many patient factors (like busy schedule, Jain and Gupta: Insulin degludec not remembering to take injection, etc) can lead to wide variability in the dosing interval and suboptimal results in fasting glucose control. These challenges may be improved upon with the IDeg due to the stable and prolonged time-action profile of IDeg coupled with low within-subject pharmacodynamic variability, allowing for a more flexible once-daily dosing time. [20] Side Effects Hypoglycemia The rates of overall confirmed hypoglycemia (PG <3.1 mmol/l or severe episodes requiring assistance) were significantly lower with degludec than glargine in type 2 diabetes, as were the rates of nocturnal confirmed hypoglycemia in both type 1 and type 2 diabetes. The lower rates of nocturnal hypoglycemia can be explained by an evenly distributed exposure (approximately 50:50) to degludec in the first and second 12-h period after once-daily administration. In contrast, 60% of exposure to glargine occurs in the first 12 h, which can lead to more nocturnal hypoglycemia after bed-time dosing as compared with morning administration. A second explanation for the lower hypoglycemic rates in these trials lies in the variability of insulin absorption from subcutaneous tissue. Subcutaneous administration of currently available exogenous insulin does not always result in a uniformly reproducible metabolic effect, even when injected at the same dose under comparable conditions. IDeg has a significantly more predictable glucose-lowering effect than glargine. In both trials, nocturnal hypoglycemia only contributed to 10-15% of all confirmed hypoglycemic events. Most of the hypoglycemic episodes occurred during day-time hours, probably attributed to the bolus mealtime insulin aspart. [23] Weight gain One of the common patient barriers to insulin intensification is weight gain. The present studies showed similar mean weight gain in both the treatment groups in patients with type 1 diabetes [1.8 kg (standard error 0.2) with degludec and 1.6 kg (0.3) with glargine, P = 0.62] and with type 2 diabetes [3.6 kg (standard deviation 4.9) with degludec and 4.0 (4.6) with glargine]. The weight gain in patients with type 2 diabetes might be partly ascribed to the increase in total daily insulin doses, including both basal and bolus insulins, throughout the trial. However, total daily insulin doses decreased in those with type 1 diabetes, Journal of Mahatma Gandhi Institute of Medical Sciences September 2013 Vol 18 Issue 2

5 Jain and Gupta: Insulin degludec 107 suggesting other contributing factors to the weight gain. [21-23] Cardiovascular (CV) events IDeg was approved by the European Commission in January 2013 following positive results from clinical trials evaluating its safety and efficacy against other long-acting insulin analogues (IGlar and insulin detemir). Much of the discussion by FDA at the November 2012 hearing surrounded an evident signal of an increased risk for major adverse CV events (MACE) with IDeg. Moreover, recently, FDA did not approve IDeg due to it CV side effects. Four major adverse CV events were reported in the type 1 diabetes trial, [21] of which three were fatal. One sudden death was attributed to the treatment of IGlar and aspart, whereas two reported fatal myocardial infarctions in the degludec group were deemed to be causally unrelated to treatment. Nonetheless, hypoglycemia-induced prolonged QT interval is a potential risk factor for sudden death in diabetes and should not be overlooked. Conclusion IDeg, an ultra-long-acting basal insulin analog, possesses several desirable attributes. Findings from clinical trials have demonstrated that the new-generation once-daily basal IDeg provides similar A1C control as compared to IGlar, both administered as basal-oral therapy or in combination with insulin aspart, with the added benefit of lower rates of hypoglycemia, particularly nocturnal hypoglycemia. IDeg has also been shown to offer dosing flexibility, with administration at any time of the day without compromising glycemic control or safety. IDeg, pending FDA approval, will be an additional treatment to help patients with T1DM or T2DM achieve glycemic control. References 1. Wang F, Surh J, Kaur M. Insulin degludec as ultra long-acting basal insulin once a day: A systematic review. Diabetes Metab Syndr Obes 2012;5: Pandyarajan V, Weiss MA. Design of non-standard insulin analogs for the treatment of diabetes mellitus. Curr Diab Rep 2012;12: Kalra S, Baruah MP, Niazi AK. Degludec: A novel basal insulin. Recent Pat Endocr Metab Immune Drug Discov 2012;6: Robinson JD, Neumiller JJ, Campbell RK. Can a new ultra-longacting insulin analogue improve patient care? Investigating the potential role of insulin degludec. Drugs 2012;72: Gough SC, Harris S, Woo V, Davies M. Insulin degludec: Overview of a novel ultra long-acting basal insulin. Diabetes Obes Metab 2013;15: Nasrallah SN, Reynolds LR. Insulin Degludec, the new generation basal insulin or just another basal insulin? Clin Med Insights Endocrinol Diabetes 2012;5: Tahrani AA, Bailey CJ, Barnett AH. Insulin degludec: A new ultra-long acting insulin. Lancet 2012;379: Meneghini L, Atkin S, Gough SC, Raz I, Blonde L, Shestakova M, et al. 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, treatto-target trial in people with type 2 diabetes. Diabetes Care 2013;36: Owens DR. Insulin preparations with prolonged effect. Diabetes Technol Ther 2011;13(Suppl 1):S Heise T, Hermanski L, Nosek L, Feldmann A, Rasmussen S, Stryhn TK, et al. Insulin degludec: Less pharmacodynamic variability than insulin glargine under steady-state conditions. Diabetologia 2010;53(Suppl 1):S Birkeland KI, Home PD, Wendisch U, Ratner RE, Johansen T, Endahl LA, et al. Insulin Degludec in Type 1 Diabetes: A randomized controlled trial of a new-generation ultra-longacting insulin compared with insulin glargine. Diabetes Care 2011;34: Heller S, Huiling P, Russell-Jones D. Insulin degludec, an ultra-longacting 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, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379: Zinman BG, Rao PV, Thomas N. Insulin degludec, an ultralong-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: Niskanen L, Leiter LA, Franek E, Weng J, Damci T, Muñoz- Torres M, et al. Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes: A randomised trial. Eur J Endocrinol 2012;167: Heise T, Tack CJ, Cuddihy R, Davidson J, Gouet D, Liebl A, et al. A new-generation ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naïve people with type 2 diabetes: A randomized, controlled trial. Diabetes Care 2011;34: Zinman B, Fulcher G, Rao PV, Thomas N, Endahl LA, Johansen T, 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: Nishimura E, Flack HB, Carsten S. Insulin degludec is a new generation ultra-long acting basal insulin designed to maintain full metabolic effect while minimizing mitogenic potentital, Ratner RE, Gough SC, Mathieu C, Del Prato S, Bode B, Mersebach H, 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. 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6 108 Jain and Gupta: Insulin degludec 19. Freemantle N, Meneghini L, Christensen T, Wolden ML, Jendle J, Ratner R. Insulin degludec improves health-related quality of life (SF-36( )) compared with insulin glargine in people with type 2 diabetes starting on basal insulin: A meta-analysis of phase 3a trials. Diabet Med 2013;30: King A. Advances in insulin therapy: A review of insulin degludec. J Fam Pract 2012;61(5 Suppl):S Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, et al. Insulin degludec, an ultra-longacting 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, open-label, treat-to-target noninferiority trial. Lancet 2012;379: Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz- Torres M, et al. Insulin degludec, an ultra-longacting 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: Hui E, Lam KS. In search of the ideal basal insulin: Does the new-generation ultra-long-acting insulin, degludec, provide the answer? J Diabetes Investig 2013;4: How to cite this article: Jain VV, Gupta O. Insulin degludec. J Mahatma Gandhi Inst Med Sci 2013;18: Source of Support: Nil, Conflict of Interest: None declared. Staying in touch with the journal 1) Table of Contents (TOC) alert Receive an alert containing the TOC when a new complete issue of the journal is made available online. To register for TOC alerts go to 2) RSS feeds Really Simple Syndication (RSS) helps you to get alerts on new publication right on your desktop without going to the journal s website. You need a software (e.g. RSSReader, Feed Demon, FeedReader, My Yahoo!, NewsGator and NewzCrawler) to get advantage of this tool. RSS feeds can also be read through FireFox or Microsoft Outlook Once any of these small (and mostly free) software is installed, add as one of the feeds. Journal of Mahatma Gandhi Institute of Medical Sciences September 2013 Vol 18 Issue 2