Diabetol Int (2014) 5:74–77 DOI 10.1007/s13340-013-0154-7
SHORT COMMUNICATION
A randomized crossover study of the efficacy and safety of switching from insulin glargine to insulin degludec among patients with type 1 diabetes Kentaro Yamada • Hitomi Nakayama • Shuichi Sato • Yuji Tajiri • Hiroh Kaku • Ichiro Tokubuchi • Tamotsu Kato Eri Soejima • Tsuyoshi Ohki
•
Received: 14 August 2013 / Accepted: 24 November 2013 / Published online: 3 January 2014 Ó The Japan Diabetes Society 2013
Abstract The purpose of this study was to assess the efficacy of insulin degludec compared with insulin glargine and to find a safer way of switching from insulin glargine to insulin degludec. By use of a crossover design we compared preprandial blood glucose levels for patients with type 1 diabetes when insulin glargine or insulin degludec was injected in combination with pre-meal rapidacting insulin. Insulin degludec was given before dinner at the same dose as insulin glargine to patients receiving insulin glargine once per day. When insulin glargine was given twice per day, the dose of insulin degludec was reduced by 20 % of the total dose of insulin glargine. We could safely replace insulin glargine with insulin degludec by use of this procedure without occurrence of severe hypoglycemia. There was no difference in fasting plasma glucose levels between insulin glargine and insulin degludec, indicating the appropriateness of the insulin degludec dose. However, blood glucose levels before lunch were lower when insulin degludec was used. Furthermore, the frequency of mild hypoglycemia was slightly higher before lunch in the period of insulin degludec injections, although the difference was not statistically significant. Thus, in type 1 diabetes, insulin degludec more effectively reduces glucose levels before lunch than does insulin glargine, probably as a result of steady supply of basal insulin. The potential risk of hypoglycemia before lunch may be reduced by reducing the morning dose of bolus insulin. For
K. Yamada (&) H. Nakayama S. Sato Y. Tajiri H. Kaku I. Tokubuchi T. Kato E. Soejima T. Ohki Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan e-mail:
[email protected]
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patients prone to hypoglycemia, it may be prudent to start insulin degludec injections at a lower dose. Keywords Insulin glargine Insulin degludec Type 1 diabetes Crossover study Hypoglycemia
Introduction Stable replacement of basal insulin, in combination with preprandial bolus insulin injections, is pivotal to achievement of good glucose control for patients with type 1 diabetes. Insulin glargine has been the most commonly used basal insulin preparation for a decade. Recently, insulin degludec, a new, once-daily, basal insulin preparation has become commercially available in the EU and Japan. Insulin degludec has a terminal halflife of approximately 25 h, twice that of insulin glargine, and a duration of action of more than 42 h [1–3]. In phase 3 trials [4, 5], insulin degludec reduced blood glucose levels in both type 1 and type 2 diabetes patients and reduced the risk of night time hypoglycemia compared with insulin glargine, although overall confirmed hypoglycemia was not significantly different. However, it is possible the ultra-long activity of insulin degludec may result in unexpected hypoglycemia in type 1 diabetes patients who are prone to hypoglycemia after switching from insulin glargine. There is so far no approved recommendation on switching from insulin glargine to insulin degludec in basal-bolus treatment. To determine the initial dose of insulin degludec is a clinically important issue in the treatment of type 1 diabetes. The purpose of this study was to examine the efficacy of insulin degludec compared with insulin glargine as basal insulin combined with mealtime bolus insulin therapy for patients
Safe switching from glargine to degludec
with type 1 diabetes and to find a safer way to switch from insulin glargine to insulin degludec.
Subjects and methods The subjects in this study were 21 patients (nine males and 12 females; age 52 ± 15 years) with type 1 diabetes duration of 12 ± 9 years. The patients were being treated with a combination of once or twice-daily injections of insulin glargine and preprandial injections of rapid-acting insulin. Diagnosis of type 1 diabetes was made based on the presence of circulating GAD antibodies and fasting C-peptide levels \0.6 ng/ml. HbA1c levels were 7.7 ± 1.2 % at baseline. None of the patients had (pre)proliferative retinopathy or renal insufficiency. Estimated glomerular filtration rates were 82.2 ± 22.1 ml/min/ 1.73 m2. The average dose of insulin glargine was 11.8 ± 7.3 U/day (0.22 ± 0.13 U/kg/day). Fourteen subjects received an insulin glargine injection once per day before dinner, and the other seven subjects received insulin glargine injections twice, before breakfast and before dinner. The usual dose of rapid-acting insulin was 24.1 ± 10.6 U/day (0.46 ± 0.22 U/kg/day), although the dose was adjusted on the basis of carbohydrate counting. All of the patients used insulin glargine as basal insulin for at least 3 months before the study period. After informed consent was obtained, the subjects were randomly divided into two groups. Ten subjects continued receiving the combination therapy of insulin glargine and rapid-acting insulin for 2 weeks and thereafter received an insulin regimen in which insulin glargine was replaced by insulin degludec for 2 weeks. The other 11 subjects received the insulin regimen of insulin degludec and rapid-acting insulin for the first 2 weeks and then received the original therapy, including insulin glargine, for the next 2 weeks. When insulin glargine was injected once per day, we set the dose of insulin degludec equal to the dose of insulin glargine. However, for subjects who received two injections of insulin glargine, insulin degludec was injected once per day before dinner at a dose of 80 % of the total insulin glargine dose. The patients were requested to log their self-monitoring data on preprandial glucose levels every day during the study period. The patients were also asked to record their symptoms when their glucose level was \70 mg/dl or when they noticed signs of possible hypoglycemia. Reduction of the bolus insulin dose was allowed when preprandial glucose levels were \60 mg/dl. Day-to-day variability of glucose was evaluated by absolute means of daily differences (MODD) [6]. The study was approved by the ethics committee of Kurume University, and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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Statistical analysis Data are expressed as means and SD. Statistical analysis was performed by using the paired Student’s t test, and p values \0.05 were considered statistically significant.
Results After a 10-day stabilizing period of either insulin glargine or insulin degludec treatment, mean levels of preprandial glucose were determined during the period from day 11 to day 14. Insulin degludec resulted in lower glucose values before lunch, during the steady-state period, although glucose levels were not significantly different either before breakfast or before dinner (Fig. 1). Significantly different glucose values before lunch were observed for patients receiving once-daily glargine injections. Patients treated with twice-daily glargine injections also had a similar tendency after switching to insulin degludec, despite the 20 % reduction in insulin dose. Steady-state MODD was 59.8 ± 39.1 and 46.9 ± 31.6 mg/dl during insulin glargine treatment and insulin degludec treatment, respectively (p = 0.25). No severe hypoglycemia, requiring the assistance of another person, occurred during the study period. Confirmed hypoglycemia (glucose \70 mg/dl) was slightly more common during the 14-day period of insulin degludec treatment than during the period of insulin glargine injections, although the difference was not statistically significant (65 vs. 56, Fig. 2). This trend was also observed during the steady-state period from day 11 to day 14 (23 vs. 16). The increase in hypoglycemia associated with insulin degludec treatment was observed only before lunch. Three patients reduced the dose of bolus insulin during five hypoglycemic episodes (three before lunch and two before dinner). However, total steady-state dose of bolus insulin was not different between insulin glargine and insulin degludec (23.9 ± 10.6 vs. 23.8 ± 10.5 U/day). The initial doses of basal insulin were not changed in each period. Neither baseline HbA1c levels nor basal insulin rates were significantly different between subjects who reported no confirmed hypoglycemic episode and those who reported one or more confirmed hypoglycemic episodes during the period of insulin degludec treatment (Table 1).
Discussion In previous studies [4, 5, 7], participants receiving oncedaily basal insulin before the study were switched to insulin degludec in a 1:1 ratio, whereas participants on a prestudy twice-daily basal insulin regimen were switched
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a
300
Glucose value (mg/dl)
250 200 150 100
*
50 0
Breakfast
b
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Dinner
c
Glucose value (mg/dl)
300
Glucose value (mg/dl)
Fig. 1 Preprandial glucose levels for all subjects (a) and for patients who received insulin glargine once per day (b) or twice per day (c) at a steady state (days 11–14) of insulin glargine therapy (closed circles) or insulin degludec therapy (open circles), in combination with mealtime rapid-acting insulin. Means and SD, *p \ 0.05
250 200 150 100
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Number of hypoglycemic episodes
Breakfast
Lunch
40 35 30 25 20 15 10 5 0 Before lunch
Before dinner
dinner
Fig. 2 Frequency of hypoglycemia (glucose \70 mg/dl) during the periods of insulin glargine treatment (closed columns) or insulin degludec treatment (open columns) Table 1 Association between baseline HbA1c levels, basal insulin, and hypoglycemia during insulin degludec treatment Confirmed hypoglycemic episodes during insulin degludec treatment None
One or more
Baseline HbA1c (%)
7.6 ± 1.3
7.8 ± 1.0
Basal insulin (%)
32 ± 13
32 ± 10
to the total daily basal dose or lower starting doses of insulin degludec. Generally the starting dose was determined by the investigator on an individual subject basis [8]. According to the document provided with TresibaÒ insulin, the starting dose should be determined on the basis of the state of the patient when twice-daily basal insulin is
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250 200 150 100 50 0
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replaced by insulin degludec in an basal-bolus regimen. In this study basal insulin was switched from insulin glargine to insulin degludec in a 1:1 ratio for patients receiving once-daily insulin glargine, and to insulin degludec at a dose corresponding to 80 % of their daily dose for patients receiving twice-daily insulin glargine treatment before the study. We were able to replace insulin glargine with insulin degludec by use of this procedure without the occurrence of severe hypoglycemia. However, blood glucose levels before lunch were lower when insulin degludec was used. The significant reduction observed for patients receiving insulin glargine once per day could be attributable to the attenuated hypoglycemic action of insulin glargine injected before dinner, because the glucose-lowering effect of insulin glargine is maximum approximately 5 h after injection and thereafter decreases gradually [9]. The reason why the difference was not significant before dinner is unclear. The pre-dinner glucose value might have been corrected by reduction of the bolus insulin dose or ingestion of carbohydrate at hypoglycemia. For patients who received insulin glargine twice per day, the difference was not statistically significant, probably because of a constant hypoglycemic effect during the daytime. However, glucose levels also tended to be lower before lunch and before dinner among patients who had received insulin glargine twice per day, despite a 20 % reduction in the insulin degludec dose. Furthermore, the frequency of hypoglycemia was slightly higher in the period of insulin degludec injections. This finding was not surprising, because insulin doses were optimized by use of insulin glargine before the
Safe switching from glargine to degludec
start of this study. The increase in hypoglycemia was obvious before lunch, in accordance with the reduction in mean glucose levels before lunch. To prevent hypoglycemia before lunch, it is reasonable to reduce the dose of bolus insulin before breakfast. This measure is in concordance with the report by BEGIN Basal-Bolus Type 1 Trial Investigators, who showed that mean values for daily bolus insulin dose were significantly lower, by 10 %, in the insulin degludec group compared with the insulin glargine group at the end of the phase 3 trial with type 1 diabetes patients [4]. The steady supply of basal insulin by use of insulin degludec may reduce the requirement for pre-meal rapid-acting insulin. Our observations did not ensure that pre-dinner glucose levels do not decrease as a result of switching from insulin glargine to insulin degludec. Attention should be paid to preventing not only pre-lunch but also pre-dinner hypoglycemia. Reduction of pre-lunch insulin dose may be necessary to prevent hypoglycemia before dinner for some patients. Concerning basal insulin, fasting plasma glucose levels were no different between insulin glargine and insulin degludec. No patients experienced symptomatic nocturnal hypoglycemia during the study period, although nocturnal blood glucose levels were not measured in this study. Thus, it may be appropriate to replace insulin glargine by the same dose of insulin degludec when insulin glargine is injected once per day or by 80 % of the total daily dose of insulin glargine when insulin glargine is administered twice per day. However, for patients prone to hypoglycemia, it may be prudent to start insulin degludec injections at a 10–20 % lower dose if insulin glargine is given once per day, or a 30–40 % lower dose if insulin glargine is given twice per day, and to adjust the dose on the basis of blood glucose data. Reducing the dose of insulin degludec during the initial days may be a safer way to avoid hypoglycemia soon after switching from insulin glargine. In this study there was no need to reduce insulin degludec dose from the initial doses. However, the dose of insulin degludec should be reduced if hypoglycemia occurs frequently, especially in the morning. HbA1c levels and basal insulin were not predictive for hypoglycemia after switching to insulin degludec. Although MODD was lower for insulin degludec than for insulin glargine, the difference was not statistically significant. Further studies are required to confirm that the stable pharmacodynamic property of insulin degludec is beneficial in reducing interday glucose variability. In conclusion, the observations in this study indicate that, in type 1 diabetes, insulin degludec more effectively reduces glucose levels before lunch than does insulin glargine. The initial dose of insulin degludec should be equal to or lower than the dose of insulin glargine. Dose
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reduction by 20 % or more may be appropriate for patients treated with twice-daily injections of insulin glargine. The potential risk of hypoglycemia before lunch may be reduced by lowering the morning dose of bolus insulin when switching from insulin glargine to insulin degludec. Conflict of interest Kentaro Yamada received a research grant from Sanofi; the other authors have no conflict of interest.
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