Insulin Degludec Requires Lower Bolus Insulin Doses Than Does Insulin Glargine in Japanese Diabetic Patients With Insulin-Dependent State

Abstract

Background: The study presents a comparison of the glucose-lowering effects, glycemic variability, and insulin doses during treatment with insulin degludec or insulin glargine. Methods: In this open-label, single-center, 2-way crossover study, 13 Japanese diabetic outpatients in the insulin-dependent state on basal-bolus therapy were assigned to receive either insulin glargine followed by insulin degludec, or insulin degludec followed by insulin glargine. Basal insulin doses were fixed in principle, and patients self-adjusted their bolus insulin doses. Seventy-two-hour continuous glucose monitoring was performed 2 weeks after switching the basal insulin. Results: Mean blood glucose (mg/dL) was not significantly different between insulin degludec and insulin glargine over 48 hours (141.8 ± 35.2 vs 151.8 ± 43.3), at nighttime (125.6 ± 40.0 vs 124.7 ± 50.4), or at daytime (149.3 ± 37.1 vs 163.3 ± 44.5). The standard deviation (mg/dL) was also similar (for 48 hours: 48.9 ± 19.4 vs 50.3 ± 17.3; nighttime: 18.7 ± 14.3 vs 13.7 ± 6.7; daytime: 49.3 ± 20.0 vs 44.3 ± 17.7). Other indices of glycemic control, glycemic variability, and hypoglycemia were similar for both insulin analogs. Total daily insulin dose (TDD) and total daily bolus insulin dose (TDBD) were significantly lower with insulin degludec than with insulin glargine (TDD: 0.42 ± 0.20 vs 0.46 ± 0.22 U/kg/day, P = .028; TDBD: 0.27 ± 0.13 vs 0.30 ± 0.14 U/kg/day, P = .036). Conclusions: Insulin degludec and insulin glargine provided effective and stable glycemic control. Insulin degludec required lower TDD and TDBD in this population of patients.

Keywords

clinical trial continuous glucose monitoring insulin degludec insulin glargine insulin therapy

Insulin degludec is a new-generation long-acting insulin analog that has stable and ultra-long glucose-lowering effects, as demonstrated using the euglycemic clamp technique.^1,2 It has recently been approved for the treatment of diabetes in Europe and Japan. Insulin degludec is a soluble dihexamer preparation that forms stable soluble multihexamers after subcutaneous injection. These multihexamers are retained at the injection site for a short period of time before entering the blood stream in a slow and sustained manner by gradual dissolution with releasing monomers. They also bind with albumin via a fatty acid side chain at the injection site and in the blood, increasing the duration of the action.¹

It has been reported that the frequency of nocturnal hypoglycemia was significantly lower in patients treated with insulin degludec than in patients treated with insulin glargine if overall glycemic control was equal.^3-5 However, in the Food and Drug Administration review,⁶ the advantageous effects of insulin degludec in nocturnal hypoglycemia were not apparent when patients with type 1 diabetes were analyzed alone or when the definition of the nighttime period was changed from 0:01-5:59 to 21:59-5:59 or to 0:01-7:59. Therefore, it is unclear whether insulin degludec is associated with a lower frequency of nocturnal hypoglycemia compared to insulin glargine. In addition, in a clamp study of patients with type 1 diabetes, it was reported that the day-to-day variability of the glucose-lowering effect under steady state conditions was 4 times lower in insulin degludec-treated patients than insulin glargine-treated patients.⁷ These earlier studies evaluated HbA1c, fasting plasma glucose, and 9-point self-monitoring of blood glucose (SMBG) as indices of glycemic control.^3-7 HbA1c and SMBG are standard indices of glycemic control, but do not provide detailed assessment of changes in plasma glucose throughout the day. Also, in a comparative study of continuous glucose monitoring (CGM) of Japanese patients with type 1 diabetes, it was reported that lower doses of insulin degludec achieved the equivalent glycemic control as insulin glargine.⁸ In that study, the patients consumed a test meal during CGM. However, the daily meals and activity levels of outpatients are not constant in real-life conditions. In particular, insulin-treated patients usually adjust their insulin dose according to their meal content and activity level. Therefore, it is important to compare the efficacies of various insulin analogs in real-life conditions.

The current study examined Japanese diabetic outpatients in the insulin-dependent state who were treated with insulin glargine and insulin degludec in a crossover manner to compare the glucose-lowering effects, glycemic stability, and daily insulin doses between insulin degludec and insulin glargine in everyday life.

Methods

Subjects

Diabetic patients in the insulin-dependent state, mainly with type 1 diabetes, who were treated with a basal-bolus insulin regimen at Kitasato Institute Hospital were enrolled in the study. Patients with diabetic nephropathy exceeding stage III (urinary albumin ≥300 mg/g creatinine or urinary protein ≥0.5 g/g creatinine) or with abnormally elevated aspartate aminotransferase/alanine aminotransferase (3 × the upper limit of normal) were excluded from the study. All patients received an explanation of the procedures and possible disadvantages of participating in the study and gave written informed consent before enrollment. This study was approved by the Institutional Review Board of Kitasato Institute Hospital and was performed in accordance with the principles of the Declaration of Helsinki.

Study Design

Patients were pseudo-randomly assigned to 1 of 2 sequences in which each patient’s former basal insulin was discontinued and replaced with either insulin glargine (sequence I) or insulin degludec (sequence II). After 2 weeks of treatment, the basal insulin was switched to the other insulin. Patients were asked to continue their other antihyperglycemic medications without changing their doses throughout the study.

To compare insulin degludec to insulin glargine under the same conditions, the doses of these long-acting insulin analogs were not changed. Seventy-two-hour CGM was performed ≥14 days after switching the basal insulin. The study drugs were switched the day after completing the first CGM period (Figure S1, available in the supplemental materials online). Patients were asked to continue the following rule of usual medical treatment. In usual medical practice, patients decide their bolus insulin dose based on carbohydrate insulin ratio (for 10 g of carbohydrates per 1 unit) at the time of initiation of insulin therapy. In addition, based on each preprandial SMBG, they decide the correction bolus dose from their insulin sensitivity factor. Afterward, they regulate the dose taking into account carbohydrate quantity, their lifestyle, their experience, and the target value of 100 mg/dL with SMBG. During the CGM period, patients recorded the content of their meals and their levels of physical exercise in a diary.

The CGM sensor (CGM iPro2; Medtronic, Northridge, CA) was applied to the abdominal area by a certified diabetologist. Patients were instructed to measure their capillary blood glucose using finger sticks (Medisafe Mini, Terumo, Tokyo, Japan; Accu-Chek Compact Plus, Roche Diagnostics, Tokyo, Japan) at least 4 times per day (at mealtimes and at bedtime). All patients used the CGM in outpatient settings. Patients were asked to continue their usual daily life, except to keep their lifestyles as similar as possible during both treatment periods.

Fifteen Japanese patients were enrolled in the study (10 with type 1 diabetes, 4 with slowly progressive insulin-dependent diabetes, and 1 who had undergone a total pancreatectomy). Two patients with type 1 diabetes were excluded from the analyses because of protocol violation (misuse of basal insulin). Therefore, 13 patients (6 in sequence I and 7 in sequence II) completed the study. Patient characteristics are shown in Table 1. Antibody positivity and random serum C-peptide levels of patients are shown in Table S1 (available in the supplemental materials online). The insulin type and dose of each patient before the study are shown in Table S2.

Table 1.

Patient Characteristics (Mean ± SD).

Variable	Value
n	13
Type of diabetes, type 1/SPIDDM/TP (n)	8/4/1
Males/females	7/6
Age (years)	56 ± 16
Diabetes duration (years)	13 ± 10
BMI (kg/m²)	21.1 ± 3.0
Weight (kg)	57.7 ± 7.5
HbA1c (%)	7.7 ± 0.9
HbA1c (mmol/mol)^a	61.0 ± 9.2
Random serum C-peptide (nmol/L)	0.22 ± 0.32
Anti-GAD antibody, +/-/unknown (n)^b	8/4/0
Anti-IA-2 antibody, +/-/unknown (n)^b	0/5/7
Total insulin dose (U/kg/day)	0.40 ± 0.20
Basal insulin dose (U/kg/day)	0.16 ± 0.09
Detemir/glargine/degludec (n)	1/8/4
Bolus insulin dose (U/kg/day)	0.25 ± 0.13
Frequency of basal insulin injection (n)
Twice daily	4
Once daily (morning/bedtime)	9 (2/7)
Oral glucose-lowering drugs (n)
Metformin	1
α-glucosidase inhibitor	3

Data are mean ± SD or n. GAD, glutamic acid decarboxylase; IA-2, insulinoma-associated protein-2; SPIDDM, slowly progressive insulin-dependent diabetes mellitus; TP, total pancreatectomy.

Calculated using the following formula: HbA1c (mmol/mol) = [10.93 × HbA1c (%)] – 23.50.

All 12 patients except TP.

Glycemic Control

Glycemic control was assessed in terms of mean blood glucose (MBG), preprandial blood glucose (PPBG), the area under the glucose concentration curve >140 or >180 mg/dL (AUC_{>140 mg/dL} and AUC_{>180 mg/dL}), and the percentage of time with blood glucose (BG) >140 or >180 mg/dL (t_{>140 mg/dL} and t_{>180 mg/dL}). The AUC was calculated using the trapezoidal method.

Glycemic Variability

Intraday glycemic variability over 48 hours was assessed as the standard deviation (SD) and mean amplitude of glycemic excursions (MAGE). MAGE, as described by Service et al,⁹ is probably most appropriate for detecting major glucose excursions that are calculated as the arithmetic mean of differences between consecutive peaks and nadirs, providing the differences are greater than the SD around the mean values. Day-to-day BG variability was assessed as the mean of daily difference (MODD). MODD, described by Molnar et al,¹⁰ is the mean of the absolute difference between glucose values taken at the same times on 2 consecutive days. Intraday glycemic variability during the nighttime and daytime were assessed as SD and the day-to-day variability was assessed as MODD.

Hypoglycemia

Hypoglycemia was defined as a sensor value of ≤70 mg/dL and AUC_{<70 mg/dL}. Total hypoglycemic time was calculated as total time with values of ≤70 mg/dL. Severe hypoglycemia was defined as a sensor value of ≤50 mg/dL, and severe hypoglycemic time was calculated as total time with values of ≤50 mg/dL.

Statistical Analysis

Differences between the 2 insulin analogs were analyzed using the Wilcoxon signed-rank test, unless otherwise stated. Values on days 2 and 3 were used for analyses. Nighttime was defined as 6 hours before breakfast, and daytime was defined as the remaining 18 hours. All values are mean ± SD. A P value of <.05 was considered statistically significant. SPSS software 16.0J (SPSS Japan Inc, Tokyo, Japan) was used for all statistical analyses. The nourishment components of meals recorded during the CGM period were analyzed by registered dietitians, and differences between the 2 insulin analogs were analyzed in the same manner as above.

Results

Patient Characteristics

There were no significant differences between sequence I and sequence II groups, except for age (Table S3). Because there were no carryover effects or treatment-period interactions, the data obtained in both sequences were combined for the analyses. The mean duration of dosing was 55.8 days for insulin degludec and 51.9 days for insulin glargine. There were no significant changes in BMI or glycemic control indices during the treatment periods (Table 2). There were no significant differences in nourishment components of meals recorded between the CGM periods of both treatment arms (Table S4).

Table 2.

Characteristics of Patients Treated With Insulin Degludec or Insulin Glargine (Mean ± SD).

Variable	Insulin degludec	Insulin glargine	P value
BMI (kg/m²)^a	21.1 ± 3.0	21.1 ± 3.1	1.000
HbA1c (%)^a	7.7 ± 0.7	7.7 ± 0.8	.937
HbA1c (mmol/mol)^b	60.4 ± 8.1	60.6 ± 9.1	.937
GA (%)^a	22.7 ± 4.5	23.1 ± 4.6	.556
Total daily insulin dose (U/kg/day)	0.42 ± 0.20	0.46 ± 0.22	.028
Basal insulin dose (U/kg/day)	0.16 ± 0.09	0.16 ± 0.09	.246
Bolus insulin dose (U/kg/day)	0.27 ± 0.13	0.30 ± 0.14	.036
Before breakfast (U/kg/day)	0.08 ± 0.04	0.09 ± 0.04	.172
Before lunch (U/kg/day)	0.09 ± 0.05	0.10 ± 0.06	.158
Before dinner (U/kg/day)	0.10 ± 0.05	0.10 ± 0.06	.125

Data are mean ± SD. GA, glycated albumin; HbA1c, hemoglobin A1c.

At the start of 72-hour continuous glucose monitoring.

Calculated using the following formula: HbA1c (mmol/mol) = [10.93 × HbA1c (%)] – 23.50.

Glycemic Control

MBG, PPBG, AUC_{>180 mg/dL}, AUC_{>140 mg/dL}, t_{>180 mg/dL}, and t_{>140 mg/dL}, which were calculated from CGM data, were not significantly different between the 2 insulin analogs (Table 3). The results were not affected by sex. Figure 1A shows mean daily profiles on days 2 and 3. Figure 1B shows mean daily profiles after aligning the curves from the time of injecting basal insulin in 9 patients who injected their basal insulin once daily. Basal insulin injection times and meal times of each patient are shown in Tables S5 and S6. The difference in MBG between the 2 insulin analogs was greatest at 12 hours after injection (Figure 1B). There were no significant differences in glycemic control during the nighttime or daytime between the 2 insulin analogs (Table 3).

Table 3.

Results of Continuous Glucose Monitoring (Mean ± SD).

	48 hours			Nighttime			Daytime
	Insulin degludec	Insulin glargine	P value	Insulin degludec	Insulin glargine	P value	Insulin degludec	Insulin glargine	P value
Glycemic control
MBG (mg/dL)	141.8 ± 35.2	151.7 ± 43.3	.279	125.6 ± 40.0	124.7 ± 50.4	.382	149.3 ± 37.1	163.3 ± 44.5	.152
AUC_{>180 mg/dL} (mg/dL•h)	751.0 ± 964.8	1000.4 ± 1261.7	.272	384.5 ± 1044.7	523.3 ± 999.4	.463	958.7 ± 1058.3	1249.7 ± 1480.2	.272
AUC_{>140 mg/dL} (mg/dL•h)	1510.7 ± 1462.1	1973.9 ± 1978.0	.221	850.8 ± 1668.1	1158.9 ± 1845.9	.859	1805.6 ± 1531.9	2305.6 ± 2108.3	.221
t_{>180 mg/dL} (%)	21.6 ± 18.6	29.5 ± 27.7	.117	13.0 ± 23.8	21.2 ± 33.4	.249	26.2 ± 19.9	33.5 ± 27.8	.209
t_{>140 mg/dL} (%)	39.5 ± 22.7	47.9 ± 28.7	.235	26.2 ± 30.4	31.3 ± 41.4	.721	45.3 ± 24.4	55.1 ± 27.1	.196
Glycemic variability
SD (mg/dL)	48.9 ± 19.4	50.3 ± 17.3	.600	18.7 ± 14.3	13.7 ± 6.7	.196	49.3 ± 20.0	44.3 ± 17.7	.422
MAGE (mg/dL)	96.9 ± 43.2	102.3 ± 41.9	.600	—	—	—	—	—	—
MODD (mg/dL)	49.1 ± 21.4	52.3 ± 25.0	.552	35.6 ± 31.0	44.3 ± 44.1	.152	53.3 ± 23.9	56.0 ± 26.6	.701
Hypoglycemia
Time <70 mg/dL (min)	35.2 ± 61.6	71.0 ± 89.6	.173	18.8 ± 36.8	41.3 ± 72.1	.310	47.1 ± 68.1	24.0 ± 27.6	.575
AUC_{<70 mg/dL} (mg/dL•h)	21.3 ± 35.9	41.5 ± 76.2	.646	14.6 ± 27.4	127.7 ± 270.4	.398	22.6 ± 42.7	8.1 ± 11.5	.534
Severe hypoglycemic time <50 mg/dL (min)	4.8 ± 12.5	26.2 ± 64.7	.285	0.0 ± 0.0	23.1 ± 56.4	.180	4.8 ± 12.5	0.0 ± 0.0	.109
PPBG
Before breakfast (mg/dL)	115.5 ± 31.9	128.8 ± 47.6	.433	—	—	—	—	—	—
Before lunch (mg/dL)	123.3 ± 32.5	129.9 ± 41.7	.600	—	—	—	—	—	—
Before dinner (mg/dL)	135.4 ± 71.8	151.0 ± 41.2	.382	—	—	—	—	—	—

Data are mean ± SD. AUC, area under the curve; CGM, continuous glucose monitoring; MAGE, mean amplitude of glycemic excursions; MBG, mean blood glucose; MODD, mean of daily difference; PPBG, preprandial blood glucose SD, standard deviation.

Figure 1.

(A) Twenty-four-hour glucose profiles determined on days 2 and 3 of 72-hour continuous glucose monitoring. Each point represents mean ± SD of 13 patients treated with insulin degludec (white circles) or insulin glargine (black squares). (B) Glucose profiles aligned from the time of injecting the basal insulin. Each point represents mean ± SD of 9 patients who injected insulin degludec (white circles) or insulin glargine (black squares) once daily.

Glycemic Variability

SD, MAGE, and MODD values were not significantly different between the 2 insulin analogs (Table 3). There were no significant differences in indices of glycemic variability during the nighttime and daytime between the 2 insulin analogs (Table 3).

Insulin Dose

The total daily insulin dose (TDD; U/kg/day) and the total daily bolus insulin dose (TDBD; U/kg/day) were significantly lower during treatment with insulin degludec than during treatment with insulin glargine (TDD: 0.42 ± 0.20 vs 0.46 ± 0.22 U/kg/day, P = .028; TDBD: 0.27 ± 0.13 vs 0.30 ± 0.14 U/kg/day, P = .036; Table 2). The mean total basal insulin dose was identical for both insulin analogs.

Hypoglycemia

There were no significant differences between the 2 insulin analogs in terms of overall hypoglycemic parameters. The absence of differences remained after dividing the results into nighttime and daytime groups. Severe hypoglycemic time was also similar between the 2 insulin analogs (Table 3).

Discussion

We compared the glucose-lowering effects, glycemic stability, and insulin doses of insulin degludec and insulin glargine using CGM to assess glycemic and hypoglycemic indices. Because the lifestyles of outpatients vary, the meals and activities were not standardized to ensure that the results were representative of real-life conditions.

There were no significant differences between insulin degludec and insulin glargine in terms of glycemic control, glycemic variability, and hypoglycemic indices. These results are inconsistent with those of prior studies, which report that the frequency of nocturnal hypoglycemia was significantly lower with insulin degludec than with insulin glargine, despite equivalent glycemic control.^3-5 The differences in results between the previous studies and the current study may be because hypoglycemia was evaluated over different periods of time (including asymptomatic hypoglycemia) in this study using CGM, whereas SMBG was used in the prior studies. It is important to consider asymptomatic hypoglycemia when comparing hypoglycemic variables because it often occurs in elderly patients and in patients with repeating hypoglycemia. In addition, a prior study reported that the intraday variability of the glucose-lowering effect was smaller with insulin degludec than with insulin glargine,⁷ but the authors performed only hyperinsulinemic-euglycemic clamps. Our results suggest that these differences do not have a substantial impact on glycemic control in real-life conditions where meals and activities cannot be standardized.

In the present study, indices of glycemic control measured during the day tended to show a lower tendency in the insulin degludec treatment period compared with the insulin glargine treatment period (Table 3). Considering that this might be a clinically important difference, although not statistically significant, we visually inspected the 24-hour glucose profiles. Most of the patients who injected their basal insulin once daily did so at bedtime. As shown in Figure 1B, the glucose level was lower with insulin degludec than with insulin glargine from 9 to 23 hours after injection. These results indicate that, when injected at bedtime, insulin degludec has a stronger glucose-lowering effect in the daytime, even though the differences were not statistically significant. In addition, considering the timing of the trough of blood glucose, it appears that the peak action of insulin degludec is 12-13 hours after injection, as compared with 5-6 hours (at the first trough) for insulin glargine.

As there were no differences in the daily doses of insulin degludec and insulin glargine, differences in the TDD were because of differences in the TDBD. Because we enrolled patients with impaired endogenous insulin secretion, they were allowed to self-regulate their bolus insulin doses for safety reasons. Considering that most patients used carbohydrate counting to adjust their bolus insulin dose, it is possible that there were differences in the correction bolus, which might depend on the PPBG level and the SMBG level, between the 2 basal insulin analogs. Although the PPBG level and the SMBG level were not significantly different, they tended to be lower with insulin degludec (Tables 3, S7). There were no significant differences in the nourishment components of meals recorded between the CGM periods for each treatment arm (Table S4). It is therefore possible that the PPBG decreased to a greater extent during treatment with insulin degludec, and that patients reduced their bolus insulin dose to compensate for this reduction in PPBG. These results imply that it is possible to maintain equivalent glycemic control by reducing the bolus insulin dose when switching from insulin glargine to the same dose of insulin degludec. Indeed, a previous study suggested that the bolus insulin requirement decreases when switching from insulin glargine to the same or a lower dose of insulin degludec.¹¹ Furthermore, in an earlier study that adjusted the basal and bolus insulin doses, the TDD and the total daily basal insulin dose were significantly lower, under equivalent glycemic control, with insulin degludec than with insulin glargine.³ Although a direct comparison is impossible because we used a fixed basal insulin dose, it is possible that the TDD is lower with insulin degludec than with insulin glargine under equivalent glycemic control conditions. These results suggest that the same doses of insulin degludec and insulin glargine can achieve equivalent levels of glycemic control through reductions in the TDD and TDBD in Japanese diabetic outpatients in the insulin-dependent state.

As type 1 diabetes usually emerges in childhood or early adulthood, insulin treatment is essential for the duration of the patient’s lifetime. Even small changes in the daily dose translate into substantial changes in the patient’s total lifetime dose.

There are concerns over the opposing physiological effects of insulin, such as the promotion and restraint of arteriosclerosis. Some epidemiologic studies have revealed that hyperinsulinemia is a risk factor for coronary disease and cerebral infarction.^12-14 In addition, it was suggested that hyperinsulinemia-induced oxidative stress contributes to arteriosclerosis in low insulin-resistant states such as high obesity.^15,16 Therefore, it is necessary to carefully select what type of insulin a patient should receive, bearing in mind the possibility that an increase in the insulin dose might contribute to the progression of arteriosclerosis, especially in patients with other risk factors for arteriosclerosis (e.g., obesity, dyslipidemia, history of smoking, and hypertension). Long-term studies evaluating the relationship between both insulin analogs examined in the current study and the risk of arteriosclerosis are required.

The insulin doses used in this study differed from those in previous studies. The mean basal insulin dose was 0.16 U/kg/day and the mean TDD ranged from 0.42 to 0.46 U/kg/day. These doses were much lower than those used in earlier clinical studies (insulin glargine: 0.30-0.35 U/kg/day; insulin degludec: 0.36 U/kg/day; TDD: 0.67-0.74 U/kg/day).^17,18 These previous studies were performed in European countries or in the United States. The doses of basal insulin used in the current study were similar to those used in earlier studies of Japanese patients with type 1 diabetes (insulin glargine: 0.21 U/kg/day; insulin degludec: 0.21-0.28 U/kg/day; TDD: 0.54-0.76 U/kg/day).^8,19 The insulin doses used in the present study appear to be appropriate for Japanese diabetic patients in the insulin-dependent state.

This study had several limitations. The study was of short duration, had a small sample size, and was performed in an open-label manner because the injection devices are easy to distinguish. Despite these limitations, it is thought that the results obtained are reliable because the study was performed in a crossover manner and used CGM.

Conclusions

The results of this study suggest that insulin degludec provides effective and stable glycemic control, similar to insulin glargine, but reduces the TDD and TDBD in Japanese diabetic outpatients in the insulin-dependent state. The small sample size of the study precludes any definitive conclusions, and studies using larger populations and of longer duration are required to confirm the findings.

Footnotes

Abbreviations

AUC, area under the glucose concentration curve; BG, blood glucose; CGM, continuous glucose monitoring; GA, glycated albumin; GAD, glutamic acid decarboxylase; HbA1c, hemoglobin A1c; IA-2, insulinoma-associated protein-2; MAGE, mean amplitude of glycemic excursions; MBG, mean blood glucose; MODD, mean of daily difference; PPBG, preprandial blood glucose; SD, standard deviation; SMBG, self-monitoring of blood glucose; SPIDDM, slowly progressive insulin-dependent diabetes mellitus; TDBD, total daily bolus insulin dose; TDD, total daily insulin dose; TP, total pancreatectomy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Jonassen

Havelund

Hoeg-Jensen

Steensgaard

Wahlund

Ribel

. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29:2104-2114.

Heise

Nosek

Bøttcher

Hastrup

Haahr

. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab. 2012;14:944-950.

Heller

Buse

Fisher

. Insulin degludec, an ultra-long acting 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;379:1489-1497.

Bode

Buse

Fisher

. Insulin degludec improves glycaemic control with lower nocturnal hypoglycaemia risk than insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN(®) Basal-Bolus Type 1): 2-year results of a randomized clinical trial. Diabet Med. 2013;30:1293-1297.

Ratner

Gough

Mathieu

. 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. Diabetes Obes Metab. 2013;15:175-184.

Food and Drug Administration. Endocrine and Metabolic Drugs Advisory Committee meeting, 8 November 2012. Available at: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM330923.pdf.

Heise

Hermanski

Nosek

Feldman

Rasmussen

Haahr

. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab. 2012;14:859-864.

Kusunoki

Katsuno

Miyakoshi

. Effects of switching from insulin glargine or detemir to insulin degludec in patients with type 1 diabetes mellitus. Diabetes Ther. 2013;4:461-472.

Service

Molnar

Rosevear

Ackerman

Gatewood

Taylor

. Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes. 1970;19:644-655.

10.

Molnar

Taylor

. Day-to-day variation of continuously monitored glycaemia: a further measure of diabetic instability. Diabetologia. 1972;8:342-348.

11.

Yamada

Nakayama

Sato

. A randomized crossover study of the efficacy and safety of switching from insulin glargine to insulin degludec among patients with type 1 diabetes. Diabetol Int. 2014;5:74-77.

12.

Ruige

Assendelft

Dekker

Kostense

Heine

Bouter

. Insulin and risk of cardiovascular disease: a meta-analysis. Circulation. 1998;97:996-1001.

13.

Qiao

Tuomilehto

Eliasson

Feskens

Pyörälä

. Plasma insulin and cardiovascular mortality in non-diabetic European men and women: a meta-analysis of data from eleven prospective studies. Diabetologia. 2004;47:1245-1256.

14.

Lakka

Tuomilehto

Sivenius

Salonen

. Hyperinsulinemia and the risk of cardiovascular death and acute coronary and cerebrovascular events in men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Arch Intern Med. 2000;160:1160-1168.

15.

Katsuki

Sumida

Urakawa

. Increased oxidative stress is associated with serum levels of triglyceride, insulin resistance, and hyperinsulinemia in Japanese metabolically obese, normal-weight men. Diabetes Care. 2004;27:631-632.

16.

Urakawa

Katsuki

Sumida

. Oxidative stress is associated with adiposity and insulin resistance in men. J Clin Endocrinol Metab. 2003;88:4673-4676.

17.

Birkeland

Home

Wendisch

. Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine. Diabetes Care. 2011;34:661-665.

18.

Pieber

Treichel

Hompesch

. Comparison of insulin detemir and insulin glargine in subjects with type 1 diabetes using intensive insulin therapy. Diabet Med. 2007;24:635-642.

19.

Iwamoto

Clauson

Nishida

Kaku

. Insulin degludec in Japanese patients with type 1 diabetes mellitus: a randomized controlled trial. J Diabetes Investig. 2013;4:62-68.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.34 MB