As much as insulin is the best and most effective way of reducing glucose, it remains a very imperfect drug. Insulin’s narrow therapeutic window means that its administration can easily be too much or too little, making it one of the most dangerous drugs we prescribe.
The risk of hypoglycemia is very significant, with ninety-five percent of all endocrine emergency hospitalizations in people over the age of 65 being caused by hypoglycemia1. From a patient's perspective it represents one of the greatest concerns, often cited as the reason for avoiding injections2. For physicians it is also a barrier, as shown by a study which revealed that most physicians are afraid of increasing insulin doses out of fear of hypoglycaemia, even in patients who are uncontrolled3.
In addition to the fear of hypoglycemia, adherence to insulin treatment is difficult, and this itself also results in poorer glycemic control. An online survey of patients with type 1 and type 2 diabetes treated with insulin highlighted the significance of the problem. Of the 500 patients over half (57%) reported intentionally omitting their insulin injections, while regular omission of injections was reported by 20% of the patients questioned4. Injections may be omitted out of fear of hypoglycemia or simply due to busy unpredictable lifestyles.
The impact of nonadherence on glycemic control was highlighted in a study of patients with type 2 diabetes, where a significant inverse association was found between adherence to treatment and HbA1c5. In another study the omission of two basal insulin injections per week in patients with type 1 diabetes resulted in an increased HbA1c of 0.2%–0.3%6.
Degludec is a new insulin with a long duration of action that may help address some of these shortcomings. Insulin degludec differs from other long-acting insulin preparations in having a longer half -life, flat time–action profile (less likely to cause hypoglycemia) and less day-to-day variability (less glycemic variability).
What is Insulin Degludec?
A new basal insulin, degludec (Tregludec in Israel) has recently been brought to the market. It is identical to human insulin except one amino acid removed and a C-16 fatty diacid side chain is attached via a spacer. In solution, and in the injected form, degludec exists as dihexemers, but when injected it forms multi-hexameric chains which are responsible for its long duration of action, resulting in an extended insulin profile with a half-life of approximately 25 hours.
Initial Clinical Trials
In a randomized, open-label trial, 179 subjects with type 1 diabetes (mean A1C 8.4% and similar mean daily dose of insulin) received one of three types of once daily subcutaneous injections; degludec 600 μmol/l, degludec 900μmol/l or insulin glargine, while insulin aspart was administered at mealtimes7. After 16 weeks, mean and standard deviation of A1C and fasting plasma glucose were comparable in all 3 groups. Estimated mean rates of confirmed hypoglycemia were 28% lower for degludec 600 compared with glargine (rate ratio [RR] 0.72 [95% confidence interval (CI) 0.52–1.00]) and 10% lower for degludec 900 compared with glargine (RR 0.90 [95% CI 0.65–1.24]). When compared with nocturnal hypoglycaemia of glargine,the rates were 58% lower in degludec600 (RR 0.42 [95% CI 0.25–0.69]) and 29% lower in degludec900 (RR of 0.71 [95% CI 0.44–1.16]). The frequency and pattern of adverse events and the changes in weight were similar between insulin treatments7.
In a phase 3 trial which tested the extremes of dosing intervals8,9, patients treated with degludec were asked to alternate the timing of insulin administration to morning and evening, creating 8–40 hour intervals between doses over a 26 week period. Other individuals in the trial were randomized to either glargine given once daily according to the label, or degludeconce daily administered at the same time daily with the evening meal. Oral antidiabetic drug therapy was added to all three arms while those who were on a basal or a twice daily insulin regimen they were changed to once daily degludec or glargine. After 26 weeks, HbA1c was equally reduced in the flexible degludec arm and the glargine arm, by −1.28% and −1.26%, respectively, confirming noninferiority, while fasting plasma glucose was significantly lower in the degludec flexible arm vs glargine8. The fixed dose degludec arm had similar reductions as the flexible arm8. The rates of overall and nocturnal hypoglycemia were low and similar in all treatment groups with a trend to lower nocturnal hypoglycemia (non-significant 23% relative risk reduction) for the flexible arm. The results of this study demonstrate that degludec has the potential of dosing flexibly without compromising blood glucose control or increasing the risk of hypoglycemia8,9.
Two other phase III trials, one involving type 1 and the other type 2 diabetes patients, confirmed the efficacy and safety of degludec when used in basal bolus therapy compared with glargine10, 11. In patients with type 1 diabetes, treatment with both degludec or glargine reduced HbA1c by 0.4%, however, compared with glargine, degludec resulted in a 25% lower rate of nocturnal hypoglycemia11. In patients with type 2 diabetes, degludec and glargine were associated with similar HbA1c reductions of 1.2% and 1.3%, respectively. The risk of hypoglycemia was significantly lower with degludec compared to glargine, with an overall reduction of hypoglycemia, of 18% (p=0.036) and 25% for nocturnal hypoglycemia (p=0.040)10.
Potential advantages of using degludec
The long duration of action is helpful because it allows for increased flexibility for patients leading demanding, unpredictable lifestyles such as shift workers or frequent travelers crossing time zones. It could also be useful in situations where flexibility is needed, such as in patients for whom insulin is administered by a care taker or a third party, who may not be able to visit the patient at the same time every day or in general cases where routines can be disturbed.Furthermore, degludec could be useful in those patients who require two basal insulin injections a day.
The data from trials, and also as seen in the clinical real-life setting, suggest that the stability overnight allows for titration to better fasting glucose levels, without an increase in hypoglycemia. It is important to note that it may take a week or two to find the right dose for degludec. In addition, just as degludec can lead to better glucose levels overnight, its effect is also true during the day, meaning that often meal bolus doses should be decreased as well in order to avoid hypoglycemia..
Degludec’s formulation makes it feasible to combine it with short acting insulin and also with GLP-1 agonists in the same pen, developments which are already underway.
In conclusion, degludec offers the potential to achieve tighter glycemic control while reducing hypoglycemia, with the added benefit of having greater flexibility as to when the injection is be administered.
ד"ר מריאלה גלאנט, DMC - Diabetes Medical Center, תל אביב
רשימת מקורות
1.Budnitz et al., N Engl J Med 2011;365:2002–12
2. Wild et al., 2007. (2007). A critical review of the literature on fear of hypoglycemia in diabetes: Implications for diabetes management and patient education. Patient Education and Counseling, 68, 10–15.
3. Peyrot et al., Diabetic Med 2012;29:682–9
4. Peyrot M., Rubin R.R., Kruger D.F., Travis L.B. (2010) Correlates of insulin injection omission. Diabetes Care33: 240–24
5. Donnelly et al. Adherence to insulin and its association with glycaemic control in patients with type 2 diabetes. QJM 100: 345–350
6. Randlov and Poulsen, 2008. How much do forgotten insulin injections matter to hemoglobin a1c in people with diabetes? A simulation study. J Diabetes SciTechnol 2: 229–235
7. Birkeland K.I., Home P.D., Wendisch U., Ratner R.E., Johansen T., Endahl L.A., et al. (2011a) Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine. Diabetes Care 34: 661–665
8. Atkin et al., 2011, (2011) Insulin degludec does not compromise efficacy or safety when given in a flexible once-daily dosing regimen compared to insulin glargine once daily at the same time each day in type 2 diabetes. Diabetologia 54 (Suppl. 1): 542
9. Birkeland, Raz I., Gough S., Atkin S.L., Shestakova M., Blonde L., et al. (2011b) Insulin degludec in a flexible daily dosing regimen provides similar glycaemic control without increasing rates of hypoglycaemia compared to dosing the same time daily in type 2 diabetes. Diabetologia 54 (Suppl. 1): S423 (1041-P)10. Hollander et al., 2011
11. Russell-Jones D., Francisco A.M.O., Pei H., Heller S. (2011) Basal-bolus therapy with insulin degludec improves long-term glycaemic control with less nocturnal hypoglycaemia compared with insulin glargine in type 1 diabetes. Diabetologia 54 (Suppl. 1): S425 (1045-P).