An open label study switching insuline.pdf

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ORIGINAL ARTICLE

An Open-label Longitudinal Study on the Efficacy ofSwitching from Insulin Glargine or Detemir to Degludec

in Type 2 Diabetes Mellitus

Ippei Kanazawa 1, Masakazu Notsu 1, Ken-ichiro Tanaka 1, Nobuaki Kiyohara 1,Yuko Tada 2 and Toshitsugu Sugimoto 1

Abstract

Objective Insulin degludec (IDeg), a new long-acting basal insulin, and FlexTouch, a new injection device,recently became available in Japan. The efficacy and usefulness of IDeg and FlexTouch, compared with insu-lin glargine or detemir, were assessed in patients with type 2 diabetes mellitus.Methods We performed an open-label longitudinal trial in 20 patients. After informed consent was ob-tained, all subjects recorded their self-monitoring data of the blood glucose (BG) level; thereafter, basal insu-lin was replaced by an IDeg-prefilled FlexTouch with the same dose and duration of time (2 weeks). Afterusing FlexTouch, the patients were provided a device-specific questionnaire.Results The patients were divided into two groups according to the dose of basal insulin (10 U and

Intern Med 54: 1591-1598, 2015 DOI: 10.2169/internalmedicine.54.3993

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Figure1.Study protocol. Basal insulin treatment was switched to insulin degludec for 2 weeks. In the week indicated by the asterisk, self-monitored blood glucose levels were recorded every day before breakfast and just before basal insulin injection.

0

*

Insulin degludec

1 2 3 4 5

* *

weeks

Insulin glargine/detemir Insulin glargine/detemir

Recently, insulin degludec (IDeg), a new, long-acting ba-sal insulin preparation, has been made commercially avail-able. IDeg is reported to have a terminal half-life of ap-proximately 25 hours, which is two times longer than insu-lin glargine, and a duration of action of more than 42hours (2, 3). In addition, IDeg provides a smaller peak ef-fect compared with traditional basal insulin (4) and thusmay be an ideal basal insulin to achieve the stable control ofthe BG levels.As insulin devices have developed, it has become easier

to initiate insulin therapy than before. It has become easierto teach diabetic patients how to use insulin injection pens;therefore, the use of these pens is widespread. Owing tocontinuous improvements in the injection-system technology,a prefilled injection device, FlexTouch, was newly generatedby Novo Nordisk A/S (Kobenhavn, Denmark). It has beenreported that more insulin-treated pen-naive patients withtype 1 and type 2 diabetes mellitus preferred FlexTouch interms of the ease of use, insulin injection, diabetes manage-ment, and overall preference (5). In 2013, the IDeg-prefilledFlexTouch became available in Japan; however, the efficacyof IDeg or the usefulness of FlexTouch has not yet beenclinically evaluated in patients with type 2 diabetes. Weherein evaluate the BG levels and their fluctuations in Japa-nese patients with type 2 diabetes during the use of tradi-tional basal insulin and IDeg and determine the usefulnessof FlexTouch via interview forms when the previous injec-tion device was switched to FlexTouch.

Materials and Methods

Subjects

Twenty participants with type 2 diabetes (mean age, 67.1years; 65% men) were recruited in this open-label longitudi-nal study to evaluate the efficacy of IDeg compared withtraditional basal insulin. At the study enrollment, the demo-graphic data, clinical characteristics, and current diabetestreatments were recorded. The numbers of patients who hadbeen taking sulfonylurea, metformin, dipeptidyl peptidase-4inhibitors, and alpha-glucosidase inhibitors were 1, 4, 9, and2, respectively. During the follow-up period, no prescribedmedications except for basal insulin were changed, and norestrictions were imposed on the patients lifestyle, exceptthat they were encouraged to adhere to an appropriateweight-control program, including proper nutrition control

and regular exercise.This study was in compliance with the Declaration of

Helsinki and was approved by the Institutional ReviewBoard of the Shimane University Faculty of Medicine. Allsubjects agreed to participate in the study and gave informedconsent.

Study protocol

After informed consent was obtained, all subjects contin-ued receiving insulin glargine or detemir once per day;thereafter, basal insulin was replaced by the same dose ofIDeg for the same duration of treatment (2 weeks). The pa-tients were requested to record their self-monitoring data ofthe fasting BG (FBG) before breakfast and the BG level justbefore injection of basal insulin (BG-I) for the week imme-diately prior to the switch to IDeg and for the second weekafter the switch to IDeg (Fig. 1). The means of the BG lev-els and standard deviation (SD) were calculated. The pa-tients were also asked to record their symptoms when theglucose level was


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Table1.Background Data of the Subjects.

Number of subjects (male/female) Age (years) Duration of diabetes (years) Duration of insulin treatment (years) Preparation of basal insulin Glargine Detemir Dose of basal insulin (units) Basal and 3 mealtime rapid-acting insulin Basal and 1 or 2 rapid-acting insulin Basal without bolus insulin BMI (kg/m2) Grip power (kg) ALT (U/L) Serum creatinine (mg/dL) Mean of FBG (mg/dL) SD of FBG Mean of BG-I (mg/dL)SD of BG-I HbA1c (%)

67.1 15.9

7.3

12

25.3 28.9

240.82 134

17158

287.3

20 (13/7)

164120 8

Data are mean SD. BMI: body mass index, ALT: alanine aminotransferase, FBG: fasting blood glucose, SD: standard deviation, BG-I: blood glucose before injection of basal insulin, HbA1c: hemoglobin A1c

8.9 10.7 7.5

8

4.2 9.8 140.21 271548180.9

using the paired Students t-test. Students t-test and the 2test were used in univariate analyses. All the analyses wereperformed using the statistical computer program StatView(Abacus Concepts, Berkeley, USA) and statistical signifi-cance was considered to exist at p value


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Table2.Chronological Changes in the Parameters of Blood Glucose in All Subjects.

Mean of FBG (mg/dL) SD of FBG Mean of BG-I (mg/dL) SD of BG-I

13417

15828

Baseline

27154818

13516

15022

32105213

13318

16426

25176518

Degludec After Mean change 95% CI p

0.8-1.4 -7.7 -5.5

-9.4 - 10.9-6.4 - 3.6 -19.1 - 3.7 -11.7 - 0.7

0.879 0.566 0.174 0.078

Data are mean SD. FBG: fasting blood glucose, SD: standard deviation, BG-I: blood glucose before injection of basal insulin, CI: confidential interval Statistical significance was determined using paired Students t test compared to baseline data.

Table3.Comparison of Various Parameters between Patients with Decreased BG-I and with Increased BG-I.

Age (years) Duration of diabetes (years) Duration of insulin treatment (years) Dose of basal insulin (units) Dose of basal insulin / body weight Basal with 3 bolus/basal without bolus BMI (kg/m2)Grip power (kg) ALT (U/L) Serum creatinine (mg/dL)Mean FBG (mg/dL)SD of FBG Mean of BG-I (mg/dL)SD of BG-I HbA1c (%)

66.3 17.0

4.2 7

0.12

22.5 34.3

200.81 132

14150

267.2

3/4

7.3 13.4 4.3 6 0.08

3.2 9.4 8 0.23 228 54200.8

Number of subjects 767.5 15.4

9.0 14

0.22

26.9 26.8

260.82 135

19162

297.3

5/8

10.0 9.5 8.5 8 0.13

3.9 9.5 160.20 301847180.9

13Increased Decreased

0.774 0.745 0.186 0.053 0.075 0.7830.022 0.156 0.400 0.974 0.850 0.539 0.613 0.813 0.839

p


Table4.Chronological Changes in the Parameters of Blood Glucose in Patients Treated with Less than or More than 10 Units of Basal Insulin.

Dose of basal insulin < 10 units (n=9)

Dose of basal insulin 10 units (n=11)

Mean of FBG (mg/dL)SD of FBG Mean of BG-I (mg/dL)SD of BG-I

14322

16432

Baseline

27184517

14318

14422

34104010

14322

15832

28144516


0.5 -3.5 -19.6 -10.4

-17.9 - 19.0 -13.0 - 5.9 -30.2 - 9.0 -19.5 - 1.2

0.949 0.423 0.002 0.031

Data are mean SD.FBG: fasting blood glucose, SD: standard deviation, BG-I: blood glucose before injection of basal insulin, CI: confidential interval Statistical significance was determined using paired Students t test compared to baseline data.

Mean of FBG (mg/dL) SD of FBG Mean of BG-I (mg/dL) SD of BG-I

12311

15022

Baseline

247 5419

12412

15723

269 6617

12214

15118

23157315


1.0 1.2 6.9 0.4

-9.3 - 11.3 -1.3 - 3.7

-13.0 - 26.7 -7.5 - 8.4

0.828 0.295 0.4460.901

Discussion

In this study, neither parameter was significantly changed

after switching to IDeg when the glucose levels and SDswere examined in all the subjects. These findings suggestthat switching from traditional basal insulin to IDeg may notbe useful for all patients with type 2 diabetes. However,


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Figure2.Percent changes in the blood glucose parameters before basal insulin injection. The sub-jects were divided into two groups according to the dose of basal insulin (10 U and


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Figure3.The subjects comparison assessments via a device-specific questionnaire on FlexTouch and the previously used device. The black bars indicate the number of subjects rating FlexTouch with the higher score; gray bars indicate the number of subjects rating the other device with the higher score; and white bars indicate the number of subjects who gave both the devices the same rating.

4

6

5

2

1

2

5

5

6

7

8

3

3

1

11

8

8

10

16

18

12

19

9

3

4

4

3

2

4

5

5

1

3

7

12

11

15

17

15

2

2

1

1

5

2

1

1

3

13

16

20

19

18

16

20

9 9 2

Pen Preparation before injectionEase of reading dose scale Q1

Ease of hearing clicks while setting dose Q2 Ease of feeling clicks while setting dose Q3

Ease of turning dose selector Q4 Confidence of setting correct dose Q5

Ease of attaching needle Q6 Confidence correctly performing air shot Q7

Speed of preparing pen for injection Q8

Insulin injection with PenEase of pushing injection button Q9

Ease of holding pen stable during injection Q10 Ease of determining if full dose is injected Q11

Ease of injecting in different places on body Q12 Painlessness of self-injection Q13

Fit in hand during injection Q14

General opinion about the PenConfidence in injecting correct amount of insulin Q15

Usefulness of color coding to indicate insulin type Q16 Comfort in managing daily injections Q17

Comfort in controlling blood glucose levels Q18 Pen is discreet to use in public Q19

Convenience of pen size Q20 Easy to learn how to use Q21

Overall

FlexTouch Previous Pen Both Preference

Figure4.The subjects comparison assessments via a device-specific comparative preference ques-tionnaire on FlexTouch and the previously used device. The black bars indicate the number of sub-jects rating FlexTouch with the higher score; gray bars indicate the number of subjects rating the other device with the higher score; and white bars indicate the number of subjects who gave a similar rating for both devices.

FlexTouch Previous Pen Both Preference

Easier to prepare before injection Q1

Easier to injection dose Q2

Easier to depress button for injection Q3

More suitable length when injecting maximum dose Q4

Simpler to use Q5

Easier to use Q6

Trust more to accurately deliver insulin Q7

Safer to operate Q8

1

5

9

4

5

3

3

4

8

7

1

4

5

6

5

15

7

4

19

12

10

11

12

tween the effect of IDeg and the residual capacity of insulinsecretion as well as the dose of basal insulin in type 2 dia-betes.Conversely, the FBG levels remained unchanged after the

switch to IDeg. Phase 2 and 3 trials have shown similar re-sults to the present study. The lowering effects of IDeg andglargine on the FBG and HbA1c levels were not different inthe patients with type 2 diabetes (7, 8). However, it has


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Table6.Comparison of Various Parameters between the Preference of Insulin Device.

Age (years) Male/female Duration of diabetes (years) Duration of insulin treatment (years) Dose of basal insulin (units) Basal with 3 bolus/basal without bolus BMI (kg/m2)Grip power (kg) Mean FBG (mg/dL)SD of FBG Mean of BG-I (mg/dL)SD of BG-I HbA1c (%) Changes in mean FBG (mg/dL)Changes in SD of FBG Changes in mean of BG-I (mg/dL)Changes in SD of BG-I

7 / 2

3 / 6

Number of subjects

6 / 3

8 / 1

FlexTouch Previous Pen p


65.4

10.3 4.6 13

25.9 31.6 123

13151

257.2

8 0

-13-4

9.8

7.5 5.6 10

3.7 8.2 278 48151.0 249 1210

67.2

21.2 10.2

10

24.9 29.1 149

23173

347.5 -2 -3 0

-8

7.6

11.9 8.9 6

5.3 10.7 222050200.8 18143317

0.674 0.599 0.0340.140 0.490 0.016 0.648 0.611 0.039 0.198 0.352 0.308 0.446 0.3190.588 0.268 0.633

9 9

been previously reported that the events of nocturnal hypo-glycemia were significantly reduced in the patients treatedwith IDeg compared with those treated with insulinglargine (8). The glucose-lowering effects of insulin glargineand detemir last a maximum of approximately 4 and 7hours, respectively, after injection and then decrease gradu-ally (9). The peak effects of glargine and detemir may causenocturnal hypoglycemia. In contrast, the glucose-loweringeffects of IDeg are reported to be flat and stable over 24hours when measured by the euglycemic glucose clampmethod (4). Therefore, switching from conventional basalinsulin to IDeg may be beneficial even if the FBG andHbA1c levels do not change. Because no hypoglycemicevents were reported in the present short-term study of rela-tively poorly controlled patients, further studies are neededto examine this point in the future.The stability effect of IDeg is clinically useful for control-

ling daily BG levels. If a patients BG levels are constantlyfluctuating, it is difficult to change the insulin administrationdose. In contrast, adjusting the insulin dose becomes easierif the BG levels are stabilized. Previous studies have shownthat the BG fluctuation improved after replacing insulinglargine with IDeg (10). As described previously, the stabil-ity of IDegs action leads to a stable BG. In the presentstudy, the SD value of BG-I was significantly decreased af-ter switching from basal insulin to IDeg in the patientstreated with a higher dose; thereafter, it returned to the base-line level. Therefore, these findings confirm the stableglucose-lowering effect of IDeg in the patients with type 2diabetes.Previous studies demonstrated that FlexTouch accurately

and consistently delivered insulin (11). Moreover, FlexTouchis currently the only prefilled pen that has a push button thatdoes not extend at any dose (as opposed to the traditional

prefilled pens which require more thumb or finger pressurefor injection). This may make it easier for patients to injectinsulin. In the present study, we evaluated the preference forFlexTouch when the insulin device was exchanged for 2weeks. Half of the patients preferred FlexTouch comparedwith the previous device they used and half did not. In addi-tion, the patients with a shorter duration of diabetes, singleinsulin injection, and lower FBG levels tended to preferFlexTouch compared with their previous insulin device. Inother words, the patients with a longer duration of diabetesreceiving basal and three bolus mealtime rapid-acting insulintreatments may have become more accustomed to the insulindevice they were using. However, the insulin device prefer-ence made no difference in the glucose-lowering effect ofIDeg.There are some limitations associated with the present

study. First, the sample size was not large enough to makedefinite conclusions. A large-scale study ought to be con-ducted to confirm the present findings. However, we chrono-logically evaluated the BG levels and SDs after switchingfrom IDeg to the previous insulin and found that the pa-rameters evaluated returned to the baseline levels. Thesefindings support the effectiveness of IDeg. Second, we ana-lyzed only subjects who accepted the study protocol; there-fore, we are not able to exclude potential selection bias.Third, due to the limited number of subjects, we could notseparately assess insulin glargine and detemir. Fourth, theBMIs in the present populations were lower than those ob-served in Western populations, and the capacity of insulinsecretion and degree of obesity in Asian populations areknown to differ from Western populations (12). Thus, large-scale longitudinal studies should be performed in othercountries. In contrast, previous studies showed no differ-ences in the BG levels between IDeg and glargine (7, 8).


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We found that the BG-lowering effects of high-dose IDegmay be more favorable than traditional basal insulin. Thecontradictory results between the previous studies and thepresent study may be due to the differences in the studyprotocol, basal insulin doses, and insulin injection devices.In conclusion, replacing basal insulin with IDeg is useful

for the stable and accurate control of the BG levels in thepatients with type 2 diabetes receiving higher doses of basalinsulin. The patients with a short duration of diabetes re-ceiving a single injection of insulin preferred switching fromtheir device to FlexTouch.This manuscript has been registered with an approved IC-

MJE clinical trial registry ID (UMIN000011333).

The authors state that they have no Conflict of Interest (COI).

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1. UKPDS Group. U.K. prospective diabetes study 16. Overview of6 years therapy of type II diabetes: a progressive disease. U.K.Prospective Diabetes Study Group. Diabetes 44: 1249-1258, 1995.

2. Heise T, Pieber TR. Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based onisolycaemic clamp studies. Diabetes Obes Metab 9: 648-659,2007.

3. Heise T, Hvelmann U, Nosek L, Bttcher S, Granhall C, HaahrH. Insulin degludec has a two-fold longer half-life and a moreconsistent pharmacokinetic profile than insulin glargine. Diabetes60 (Suppl 1): LB11, 2011.

4. Heise T, Nosek L, Bttcher SG, Hastrup H, Haahr H. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering ef-fect in type 2 diabetes. Diabetes Obes Metab 14: 944-950, 2012.

5. Garg S, Bailey T, DeLuzio T, Pollom D. Preference for a new pre-filled insulin pen compared with the original pen. Cerr Med ResOpin 27: 2323-2333, 2011.

6. Yamada K, Nakayama H, Sato S, et al. A randomized crossoverstudy of the efficacy and safely of switching from insulin glargineto insulin degludec among patients with type 1 diabetes. DiabetolInt 5: 74-77, 2014.

7. Zinman B, Fulcher G, Rao PV, et al. Insulin degludec, an ultra-long-acting basal insulin, once a day or three times a week versusinsulin glargine once a day in patients with type 2 diabetes: a 16-week, randomized, open-label, phase 2 trial. Lancet 377: 924-931,2011.

8. Rodbard HW, Cariou B, Zinman B, et al. Comparison of insulindegludec with insulin glargine in insulin-nave subjects with type2 diabetes: a 2-year randomized, treat-to-target trial. Diabet Med30: 1298-1304, 2013.

9. Porcellati F, Rossetti P, Busciantella NR, et al. Comparison ofpharmacokinetics and dynamics of the long-acting insulin analogsglargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study. Diabetes Care 30: 2447-2452,2007.

10. Ogawa S, Nako K, Okamura M, Senda M, Sakamoto T, Ito S.Compared with insulin glargine, insulin degludec narrows the day-to-day variability in the glucose-lowering effect rather than lower-ing blood glucose levels. J Diabetes Mellitus 3: 244-251, 2013.

11. Wielandt JO, Niemeyer M, Hansen MR, Bucher D, Thomsen NB.FlexTouch: a prefilled insulin pen with a novel injection mecha-nism with consistent high accuracy at low-(1 U), medium-(40 U),and high-(80 U) dose settings. J Diabetes Sci Technol 5: 1195-1199, 2011.

12. Torrens JI, Skurnick J, Davidow AL, et al. Ethnic differences ininsulin sensitivity and beta-cell function in premenopaulsa or earlyperimenopausal women without diabetes: the Study of WomensHealth Across the Nation (SWAN). Diabetes Care 27: 354-361,2004.

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An open label study switching insuline.pdf