Clin Drug Investig DOI 10.1007/s40261-017-0541-0
ORIGINAL RESEARCH ARTICLE
Basal and Bolus Insulin Dose Changes after Switching Basal Insulin to Insulin Degludec in Patients with Type 1 Diabetes Mellitus: A Pilot Study Yoshiyuki Hamamoto1,3 • Sachiko Honjo1 • Kanta Fujimoto1 • Shinsuke Tokumoto1 Hiroki Ikeda1,2 • Yoshiharu Wada1 • Hiroyuki Koshiyama1
•
Ó Springer International Publishing Switzerland 2017
Abstract Background and objectives Ultra-long-acting insulin degludec (DEG) has a longer duration of action and less daily variability relative to other basal insulin (BI), and thus may benefit patients with type 1 diabetes mellitus (T1DM). We examined the impact of switching BI to DEG on glycemic control and insulin dose in T1DM. Methods T1DM patients (n = 22; six male; mean age: 64.5 ± 12.6 years) receiving basal-bolus insulin therapy were included. Initially, the BI dose was replaced with DEG in a 1:1 ratio; 80–100% of the total dose was replaced with DEG for multiple basal insulin injections. DEG was titrated according to study protocol. Changes in HbA1c, daily insulin dose, glycemic self-monitored blood glucose variations, and hypoglycemia frequency were evaluated for 24 weeks. Results Once-daily DEG significantly decreased HbA1c levels when switched from once-daily BI (7.9 ± 0.8 vs. 7.5 ± 0.9%, p = 0.020) and maintained HbA1c when switched from twice-daily BI (8.5 ± 1.6 vs. 8.4 ± 1.2%, p = 0.457). The BI dose decreased by -7.8 ± 13.9% (p = 0.017) and -16.6 ± 16.9% (p = 0.050) when switched from once-daily BI and twice-daily BI, respectively. The total bolus insulin dose significantly decreased when
switched from once-daily BI (21.7 ± 8.3 to 19.3 ± 8.8 U/day, p = 0.016) especially in the injection before breakfast and evening meal. Body weight and hypoglycemia frequency was not significantly different. Conclusion DEG improved glycemic control when switched from once-daily BI and maintained glycemic control when switched from twice-daily BI without increasing hypoglycemia.
Key Points Switching basal insulin to degludec improved glycemia and reduced basal and bolus insulin doses in patients with T1DM. The benefit of changing basal insulin to degludec was more prominent when switched from once-daily basal insulin injection. Adjustment of bolus insulin dosing was different between switching from once daily and twice daily.
1 Introduction & Yoshiyuki Hamamoto
[email protected] 1
Center for Diabetes and Endocrinology, The Tazuke Kofukai Foundation, Medical Research Institute, Kitano Hospital, Osaka, Japan
2
Ikeda Hospital, Ikeda, Hyogo, Japan
3
Present Address: Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka 553-0003, Japan
Insulin degludec, a newly developed and ultra-long-acting form of insulin, was reported to have a much longer duration of action and less day-to-day variability than other types of basal insulin. Specifically, pharmacokinetic analysis of insulin degludec identified a flat, stable profile with a terminal half-life and a duration of action exceeding 25 and 40 h, respectively [1, 2]. In addition, pharmacodynamic data revealed a fourfold decrease in day-to-day variability with insulin degludec vs. insulin glargine [3].
Y. Hamamoto et al.
These features of insulin degludec could contribute to a reduction in hypoglycemia and, therefore, might improve glycemic control and hypoglycemia prevention in patients with type 1 diabetes. In addition to a lower frequency of hypoglycemia, the longer duration of insulin degludec action might allow patients who inject basal insulin more than twice daily to reduce the number of injections, which can contribute to an improved quality of life [4]. In a previous report, injecting insulin glargine twice daily yielded better glycemic control in patients with type 1 diabetes compared to once-daily injection [5]. This was because of the insufficient action duration associated with long-acting insulin preparations that are often used as basal insulin, such as insulin glargine and insulin detemir (shorter half-life of approximately 12 h) [2], which may force patients to inject basal insulin more than twice daily to reduce glucose fluctuations and maintain stable glycemic control. Furthermore, the potential peak of action of insulin glargine and insulin detemir can cause nocturnal hypoglycemia when injected at night and may lead to the Somogyi phenomenon. For this reason, the once-daily injection of basal insulin with flat profile and longer duration of action is desirable. On the other hand, the appropriate basal and bolus insulin dosages may differ when switching basal insulin from other forms of insulin to degludec. Notably, dosage adjustment may be required, especially when switching from twice-daily injection of another basal insulin to oncedaily injection of insulin degludec. This was confirmed by the slightly higher hypoglycemia rates observed in some of the BEGIN trials during the early period after degludec initiation. However, a lower hypoglycemia rate over time, as determined by the cumulative number of hypoglycemic episodes at 4–20 weeks, was detected during longer observations with insulin degludec [6–8]. Therefore, an understanding of insulin dosing is highly important to the clinical application of degludec. To address these clinical issues, we examined the efficacy and safety of insulin degludec and the changes in insulin doses required when switching from basal insulin to degludec in patients with type 1 diabetes receiving basal-bolus insulin injection therapy.
2 Subjects and Methods 2.1 Subjects Patients who were diagnosed with type 1 diabetes mellitus at least 1 year prior to the study, receiving basal-bolus insulin therapy, and had regular visits at our clinic were enrolled. Patients with serious diabetic complications, such as advanced retinopathy, nephropathy, or neuropathy, a
history of cardiovascular events, extremely high levels of glycated hemoglobin (HbA1c; [10.5%), pregnant or breast feeding women, or an age \20 years were considered ineligible to participate. In addition, patients with a history of severe hypoglycemia and those who had experienced hypoglycemic coma were also excluded. This study was approved by the ethics committee of our institute and conducted in accordance with the Helsinki Declaration of 2008. Informed consent was obtained from all patients upon study enrollment. In addition, this study was registered in the University hospitals Medical Information Network (UMIN; No. 000010634). 2.2 Intervention Procedures Initially, the basal insulin dose was replaced with insulin degludec (Novo Nordisk Pharma, Ltd. Tokyo, Japan) in a 1:1 ratio; if basal insulin was injected more than twice daily, 80–100% of the total dose was replaced with insulin degludec. All patients received injections of insulin degludec during the evening or before bedtime, and insulin degludec was titrated according to the study protocol and fasting blood glucose levels (Table 1). In consideration of safety, the targeted fasting blood glucose levels were classified according to an age cut-off of 70 years (5.0–6.6 mmol/L for those aged B70 years; and 5.6–7.7 mmol/L for those aged [70 years). Regarding the study protocol, all patients were asked to adjust their basal insulin doses before switching to insulin degludec according to a 3-consecutive-day average of their fasting glucose levels. Bolus insulin doses were adjusted according to the protocol or by carbohydrate counting. For carbohydrate counting, the carbohydrate:insulin ratio was initially determined according to the 500 rule (i.e., 500 was divided by the total daily insulin dose to determine the amount of carbohydrates (grams) covered by 1 unit of insulin) and adjusted individually before the study. In patients not performing carbohydrate counting, bolus insulin doses were adjusted at each visit every month by attending Table 1 Basal insulin adjustment protocol Fasting plasma glucosea (mmol/L)
Dose adjustment
Age \70 years
Age [70 years
\3.3
\3.9
3.3–4.9
3.9–5.5
-2 U or -5%
5.0–6.6
5.6–7.7
0
6.7–9.9
7.8–10.0
?2
10.0–15.0
C10.0
?4
C15.0
–
?6
a
-4 U or -10%
Doses were adjusted based on the 3-day average of self-monitored blood glucose results
Improvement in Glycemic Control with Reduced Degludec Doses
physicians according to the results of self-monitoring blood glucose (SMBG), targeting blood glucose levels before each meal and at bedtime between 3.9 and 7.8 mmol/L. Patients visited our clinic 1 week after switching and every month thereafter. Adjustments or suggested adjustments to basal and bolus insulin doses were made by attending physicians. The bolus insulin doses recorded by patients were used to calculate the monthly mean insulin dose at each mealtime, and the mean insulin doses prior to the visit were treated as bolus insulin doses. The basal insulin dose was defined as the injected insulin dose at each visit. Patients performed selfmonitoring blood glucose (GlutestAce, Sanwa Kagaku Kenkyusho Co., LTD., Japan, or OneTouch Ultraview, Johnson & Johnson K. K., USA) before each meal and before bed, as well as when experiencing symptoms of hypoglycemia. Hypoglycemia was defined as a measured blood glucose level \3.8 mmol or the existence of hypoglycemia symptoms and requiring glucose supplementation; severe hypoglycemia was defined as impaired consciousness and requiring assistance from another person. 2.3 Outcomes HbA1c levels were measured and evaluated at baseline and at 4, 12, and 24 weeks after insulin degludec initiation. SMBG-determined daily insulin doses and hypoglycemia frequency were evaluated for 24 weeks. The primary endpoints were changes in HbA1c levels and the basal and bolus insulin doses at 4, 12, and 24 weeks. Secondary endpoints included the fasting glucose level, body weight, and hypoglycemia frequency. In addition to general analyses of the overall patient population, the patients were divided into two groups according to the number of daily basal insulin injections at baseline (i.e., once daily and twice daily) for further comparison. 2.4 Statistical Analysis All values were presented as means ± standard deviations unless otherwise noted. The Mann–Whitney U test was used to compare parameters between the once-daily and twice-daily injection groups, and the paired Student’s t test was used to compare parameters before and after basal insulin switching within groups. A p value of B0.05 was considered statistically significant.
3 Results 3.1 Characteristics of the Patients The 22 patients enrolled in the study were predominantly female (n = 16), and six patients were switched from a
twice-daily injection of basal insulin (Table 2). All patients used insulin glargine at baseline, except for two patients who used insulin detemir (one each for the once-daily and twice-daily groups). The mean age, body mass index, duration of diabetes, HbA1c level, fasting C-peptide concentration, and total daily insulin dose did not differ significantly between the once-daily and twice-daily groups. However, the twice-daily group tended to be older and have lower endogenous insulin secretion at baseline, suggesting that the insufficient duration of the action of conventional long-acting insulin led to multiple daily injections for maintaining glycemic control. However, despite requiring additional injections, the twice-daily group tended to use lower total daily insulin doses than the once-daily group. 3.2 Changes in Glycemic Control and Insulin Doses in Total Overall, insulin degludec significantly reduced HbA1c levels from 8.0 ± 0.9 to 7.6 ± 1.1% at 12 weeks (p = 0.014) and 7.7 ± 1.1% at 24 weeks (p = 0.025; Fig. 1a). Similarly, the fasting glucose levels also decreased significantly from 8.8 ± 2.6 to 7.3 ± 1.7 mmol/L at 12 weeks (p = 0.001) and 7.4 ± 1.7 mmol/L at 24 weeks (p = 0.026). Interestingly, these improved glycemic parameters correlated with a decrease in the total daily insulin dose from 29.0 ± 11.7 to 27.4 ± 12.3 U/day at 12 weeks (-6.2%; p = 0.017) and 26.5 ± 11.8 U/day at 24 weeks (-9.2%; p = 0.005; Fig. 1b). However, the basal insulin doses decreased gradually from 9.2 ± 4.7 to 8.6 ± 5.3 U/day at 12 weeks (-8.7%; p = 0.049) and 8.3 ± 4.6 U/day at 24 weeks (-10.2%; p = 0.005), the total daily bolus insulin doses decreased significantly from 19.9 ± 8.1 to 18.9 ± 7.8 U/day at 4 weeks (immediately after switching; p = 0.023) and remained at a similar level at 24 weeks (18.2 ± 8.3 U/day; p = 0.027; Fig. 1c). 3.3 Comparison of Glycemic Control and Insulin Doses between the Groups with Switching from Once-Daily and Twice-Daily Basal Insulin Injection According to further comparisons, although the once-daily group exhibited a significant improvement in HbA1c levels immediately after switching (from 7.9 ± 0.8% at baseline to 7.7 ± 0.7% at 4 weeks; p = 0.011) and sustained this improvement throughout the study (7.3 ± 0.8% at 12 weeks and 7.5 ± 0.9% at 24 weeks; p = 0.004 and 0.020, respectively), the twice-daily group did not exhibit any changes (8.5 ± 1.6% at baseline vs. 8.6 ± 1.1% at 12 weeks and 8.4 ± 1.2% at 24 weeks; p = 0.302 and
Y. Hamamoto et al. Table 2 Demographic and baseline characteristics
Total
Once daily
Twice daily
p value
Gender, male:female (n)
6:16
4:12
2:4
0.695
Age (years)
64.5 ± 12.6
62.1 ± 13.7
71.2 ± 5.8
0.097
Body mass index (kg/m2)
21.3 ± 4.0
21.2 ± 3.3
21.3 ± 5.9
0.631
Duration of diabetes (years)
13.3 ± 11.4
12.0 ± 10.6
16.8 ± 12.9
0.219
HbA1c (%)
8.0 ± 0.9
7.9 ± 0.8
8.4 ± 1.1
0.294
Fasting C peptide concentration (ng/ml)
0.24 ± 0.30
0.24 ± 0.20
0.06 ± 0.08
0.073
24-h urinary C peptide excretion (lg/day)
6.3 ± 6.9
8.3 ± 7.3
1.8 ± 2.0
0.034
Total daily insulin dose (U/day)
29.0 ± 11.7
31.0 ± 12.6
23.7 ± 7.0
0.051
Aspart
16
10
6
–
Lispro
5
5
0
–
Glulisine
1
1
0
–
Bolus insulin (n)
Data are presented as mean ± standard deviation. p values indicate comparisons between once-daily and twice-daily groups
0.457, respectively; Fig. 1d). The basal insulin dose gradually decreased after the switch in the once-daily group with reduction rates from baseline of -7.3 ± 11.9% at 12 weeks (p = 0.093) and -7.8 ± 13.9% at 24 weeks (p = 0.017; Table 3). The twice-daily group exhibited a rapid reduction in the basal dose at 4 weeks (-14.4 ± 16.6% from baseline, p = 0.046) that was potentially attributable to protocol differences; subsequently, the dose tended to decrease thereafter to 83.4 ± 16.9% compared with baseline at 24 weeks (p = 0.050). At baseline, the twice-daily group reported lower bolus insulin doses, which might have been attributable to a lower demand for bolus insulin as a result of the increased basal insulin dosage. In the once-daily group, the total bolus insulin dose decreased gradually; in particular, the doses before morning and evening meals decreased significantly at 12 and 24 weeks. In contrast, the twice-daily group showed a slight increase in the bolus insulin dose before lunch at 12 weeks; except for the pre-evening meal dose at 4 weeks, the remaining bolus insulin doses at other time points remained unchanged throughout the 24-week period. 3.4 Body Weight Change and Hypoglycemia With regard to other secondary endpoints, body weight did not change during the study period. In contrast, hypoglycemia tended to increase in frequency, especially during the early period after switching and in patients who had frequently experienced hypoglycemia before switching. However, there were no significant differences in the frequency (Table 4). No severe hypoglycemia episodes were observed.
4 Discussion 4.1 Impact of Switching Basal Insulin to Insulin Degludec In this study, insulin degludec improved glycemic control without increasing hypoglycemia in patients who were switched from another type of basal insulin. Notably, both the basal and bolus insulin doses were reduced in association with improved HbA1c levels, and without increasing hypoglycemia. With regard to evaluations of prior basal insulin injection patterns (i.e., once daily or twice daily), switching from basal insulin to degludec significantly improved HbA1c levels in the once-daily group; no significant changes were observed in the twice-daily group. The once-daily group was able to reduce the bolus insulin doses before morning and evening meals, whereas no significant bolus insulin dose changes were observed in the twice-daily group except for a slight reduction before the evening meal at 4 weeks and a slight increase before lunch at 12 weeks. In general, switching from basal insulin to insulin degludec improved glycemic control, particularly in patients who had injected basal insulin once daily prior to switching. This observation was concordant with previously reported results [9]. Although no significant improvement in glycemia was observed when switching from twice-daily basal insulin to once-daily insulin degludec, the switch might still benefit such patients with twice-daily basal insulin injection according to reports of an increased patient’s perceived treatment burden with the number of injections, possibly leading to skipped insulin injections [4]. Failure to maintain an insulin injection schedule leads to the deterioration of
Improvement in Glycemic Control with Reduced Degludec Doses
A
HbA1c (%)
*
*
*
*
20
24
4
Total daily insu lin dose (U/day)
B
8
12
50 §
40
§
*
30 20 10 0
4
D
12
Time(weeks)
HbA1c (%)
16
Time(weeks) C
24
Ch hange in insulin dose (U/day)
Fig. 1 a Mean glycated hemoglobin (HbA1c) levels and b total daily insulin doses for all patients over time after switching from basal insulin to degludec. c Changes in the basal (open column) and bolus insulin (closed column) doses in all patients at 4, 12, and 24 weeks. d Comparison of changes in HbA1c levels between the oncedaily (solid line) and twice-daily groups (dotted line). *p \ 0.05; § p \ 0.01 vs. baseline; and p \ 0.05 between groups
0
Time(weeks)
4
12
24
-1 -2 -3
*
§
*
-4 -5
*
-6
*
*†
§ †
4
8
12
†
*
glycemic control and might result in life-threatening complications in patients with type 1 diabetes. Insulin degludec features a flat, stable profile with a terminal half-life and duration of action that are significantly longer than those of other existing basal insulin forms. These unique properties of insulin degludec contribute to less glycemic variability [10], but raise the clinical question of how to determine the basal and bolus insulin doses when switching from basal insulin to degludec. In the present study, both basal and bolus insulin doses were gradually decreased over time in correlation with improved HbA1c levels. For example, a nearly 10% reduction in the basal insulin dose was observed at 12 weeks, suggesting that the basal insulin dose should be reduced by 10% when transitioning from basal insulin to
Time(weeks)
16
20
24
degludec. Although these changes could not be clearly attributed to the stable profile of insulin degludec or to slight differences in the receptor affinity or elimination rate, the findings suggest that longer-term insulin degludec therapy could contribute to a reduction in hypoglycemia. 4.2 Insulin Dose Adjustment when Changing Basal Insulin to Insulin Degludec A schematic model of the different effects of insulin degludec and other basal insulin forms on plasma insulin concentrations and bolus insulin doses is shown in Fig. 2. The longer-lasting effects of insulin degludec influence the bolus insulin dose injected just prior to basal insulin injection, as well as the subsequent bolus dose;
Y. Hamamoto et al. Table 3 Changes in fasting blood glucose, body weight, and basal insulin and bolus insulin doses Baseline
4 weeks Twice daily
7.7 ± 0.9
11.4 ± 3.3
Body weight (kg)
55.3 ± 9.0
54.8 ± 15.9
55.9 ± 8.5
55.2 ± 16.1
54.6 ± 7.9
55.5 ± 16.2
54.8 ± 8.5
56.1 ± 16.9
Basal-insulin dose (U/day) Bolus-insulin dose (U/day)
9.4 ± 5.2 21.7 ± 8.3
8.7 ± 3.7 15.0 ± 5.7
9.0 ± 5.8 20.3 ± 8.2§
7.8 ± 4.5* 14.9 ± 5.5
8.9 ± 5.7 19.9 ± 8.5*
7.8 ± 4.1 15.8 ± 6.6
8.6 ± 5.0* 19.3 ± 8.8*
7.3 ± 3.7* 15.4 ± 6.9
6.9 ± 3.4
5.3 ± 2.5
5.8 ± 3.1*
5.7 ± 3.2
Breakfast (U/day)
Twice daily
7.3 ± 1.1*
8.4 ± 2.3*
Once daily
24 weeks
Once daily Fasting blood glucose (mmol/L)
Once daily
12 weeks
6.7 ± 1.0*
Twice daily 8.7 ± 2.2*
Once daily 6.8 ± 1.3*
Twice daily 8.6 ± 1.8*
6.5 ± 3.3
5.3 ± 2.5
6.2 ± 3.0*
5.3 ± 2.9
6.6 ± 2.6*
4.7 ± 2.2
6.8 ± 2.9
5.2 ± 2.4*
6.8 ± 3.1
5.0 ± 2.5
7.1 ± 3.7*
4.7 ± 2.0*
6.8 ± 3.4*
5.2 ± 1.9
6.5 ± 3.4*
5.0 ± 1.8
Lunch (U/day)
7.1 ± 2.9
4.7 ± 2.2
Evening meal (U/day)
7.6 ± 3.5
5.0 ± 2.0
Data are shown as means ± standard deviations * p \ 0.05 vs. baseline §
p \ 0.01 vs. baseline
p \ 0.05 between once-daily and twice-daily groups
Table 4 Hypoglycemia frequency Total (n = 22)
Once-daily (n = 16)
Twice-daily (n = 6)
Episodes
Patients
Episodes
Patients
Episodes
Patients
Baseline
4.1 ± 5.7
11
4.4 ± 6.7
4 weeks
4.7 ± 6.5 (p = 0.310)
14
5.9 ± 7.6 (p = 0.088)
10
3.3 ± 3.1
4
3.5 ± 3.0 (p = 0.203)
12 weeks
5.9 ± 9.0 (p = 0.133)
12
7.3 ± 10.4 (p = 0.082)
4
9
4.0 ± 5.1 (p = 0.611)
3
24 weeks
5.3 ± 6.6 (p = 0.144)
14
5.7 ± 7.8 (p = 0.257)
9
4.0 ± 3.1 (p = 0.411)
5
7
The number of episodes/month and number of patients/month are shown Data are shown as means ± standard deviations p values represent comparisons with the baseline
accordingly, an insulin dose reduction is necessary when switching from once-daily basal insulin (dotted area; Fig. 2a). Theoretically, the bolus insulin dose before lunch should also be reduced (anastomosis area); however, in the 24-week observation period of the current study, only a non-significant trend toward a reduced insulin dose before lunch was observed (Table 3). In contrast, when switching from twice-daily basal insulin to once-daily insulin degludec, the bolus insulin dose at lunch should be increased to compensate for the basal insulin withdrawal effect in the morning if the basal insulin injection is shifted to once per evening (diagonal-lined area; Fig. 2b). The longer duration of action of insulin degludec can cover the demand for insulin before dinner in contrast to a bedtime injection of conventional basal insulin (horizontal lined area; Fig. 2a). However, this special property of insulin degludec can also result in evening hypoglycemia if the bolus insulin dose is not adjusted appropriately. Therefore, the results of our current study contribute to the body of knowledge regarding appropriate and safe insulin dose adjustments when using insulin degludec.
4.3 Hypoglycemia Frequency In this study, hypoglycemia frequency did not differ after switching from basal insulin to degludec. In contrast, a reduction in hypoglycemia episodes, particularly nocturnal episodes, when compared with insulin glargine in patients with type 1 and type 2 diabetes was shown in several clinical trials of insulin degludec [7, 8, 11–14]. Although the definitions of hypoglycemia and timescales for the nocturnal period used in those trials were controversial, a consistent reduction in nocturnal hypoglycemia with insulin degludec was found in a meta-analysis of six trials [15]. In the present study, patients were requested to measure blood glucose levels before meals, at bedtime, and when symptomatic. These intermittent blood glucose measurements rendered it impossible to detect all episodes of hypoglycemia, especially overnight. Therefore, the power to detect hypoglycemia in this study was limited. However, patients reported milder and less symptomatic hypoglycemia after switching to insulin degludec, which might be attributable to the flat pharmacodynamics; still, this characteristic could lead to hypoglycemia unawareness.
Improvement in Glycemic Control with Reduced Degludec Doses
Blood Insulin
A
Bolus insulin injecon Basal insulin injecon Basal insulin injecon -twice daily
Blood Insulin
B
Fig. 2 Schematic models of the differential effects of basal insulin relative to insulin degludec and other forms of basal insulin on plasma insulin concentration upon switching from a once-daily and b twicedaily basal insulin injection. The dotted line represents the schematic insulin concentration produced by the injection of basal and bolus insulin before switching. The intermittent line represents the schematic basal insulin concentration produced by an injection of insulin degludec; to achieve an increased insulin concentration using
insulin degludec, a reduction in the bolus insulin doses before breakfast and dinner was required (dotted area). Theoretically, the bolus insulin before lunch should also be reduced (anastomosis area). When switching the basal insulin from a twice-daily dosage, the bolus insulin dose at lunch should be increased to compensate for the withdrawal from the morning basal insulin if the basal insulin injection dosage has been set at once per evening (diagonally lined area)
Although no episodes of severe hypoglycemia were observed in the present study, hypoglycemia tended to increase in frequency during the early period after switching and in patients who had frequently experienced hypoglycemia before switching; insulin degludec should therefore be prescribed cautiously to those patients. It is known that older people have a higher incidence of hypoglycemia which leads to increased morbidities such as frailty and cognitive dysfunction, and mortality [16]. Therefore, we classified the targeting fasting blood glucose levels into two groups according to an age cut-off of 70 years in consideration of safety. It has also been reported that male patients older than 60 years are more likely to experience nocturnal hypoglycemia [17], but we did not classify the target blood glucose levels by gender to reduce the factors that affect insulin doses as much possible. Eventually, 70% of enrolled patients were female and no severe hypoglycemia was observed in the study.
were limited and the sample size was small. Especially for switching basal insulin from twice daily to insulin degludec, a study with a sufficiently large sample size will be needed to confirm our results. Despite the small sample size, enrolled subjects were homogenous and the results were consistent, with low variability. Secondly, this was an open-label, non-placebo-controlled study because we aimed to investigate the changes in insulin doses to determine the appropriate dose when switching from basal insulin to degludec and to determine its efficacy and safety. Consequently, it is possible that the efforts of patients and investigators to achieve the target blood glucose levels and report hypoglycemic events may have been biased. Thirdly, bolus insulin dose adjustments were mainly performed according to the protocol or carbohydrate counting with monthly advice provided by physicians. Patients with low insulin secretion levels tend to exhibit widely variable and unstable glycemic levels; therefore, it is almost impossible to predict an appropriate bolus insulin dose for precise postprandial glycemic control. Accordingly, there might be room for further adjustment. Fourthly, for the measurement of daily blood glucose levels, we used portable glucose meters, which have numerous
4.4 Limitations and Strengths of the Study This study had several limitations. Firstly, because this study was conducted in a single center, eligible subjects
Y. Hamamoto et al.
opportunities for errors. Although the patients enrolled were well trained and had already been performing (SMBG) for some years before enrollment, possible errors and failures for measuring and recording blood glucose levels could have occurred. Finally, hypoglycemia frequency was evaluated using scheduled SMBG values and nonscheduled values from symptomatic episodes. Therefore, the possibility of undetectable asymptomatic hypoglycemia, particularly nocturnal episodes, cannot be excluded.
5 Conclusion Insulin degludec improved glycemic control without increasing hypoglycemia following a switch from other forms of basal insulin in general. In particular, the benefit of changing basal insulin to insulin degludec may be greater in patients injecting basal insulin once daily. The basal insulin dose should be reduced by 10% when switching from basal insulin to degludec. Further studies involving a larger number of patients are needed to confirm our results.
3.
4. 5.
6.
7.
8.
9.
10. Acknowledgements The Center for Diabetes and Endocrinology, Kitano Hospital receives financial support from Novo Nordisk Pharma, MSD Pharmaceutical, Novartis Pharma, Daiichi-Sankyo, and Astellas Pharma. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Some of the results described herein were presented at the annual scientific meeting of the American Diabetes Association in 2014. Compliance with Ethical Standards
11.
12.
Funding No external source of funding was used to conduct this research. Conflict of interest YH has received speaker’s fees from Novo Nordisk Pharma. The other authors declare that they have no conflict of interests. No other potential conflicts of interest relevant to this study exist. Ethical approval This study was approved by the ethics committee of our institute and all procedures performed in studies involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
13.
14.
Informed Consent All participants provided informed consent upon study enrollment. 15.
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