Changes in HbA1c and hypoglycemic episodes in type 1 diabetes patients after switching to insulin glargine U300: Pilot study

Accepted Manuscript Changes in HbA1c and hypoglycemic episodes in type 1 diabetes patients after switching to insulin glargine U300: pilot study Marina Gradišer, Maja Cigrovski Berković, Ines Bilić-Ćurčić PII: DOI: Reference:

S0168-8227(16)30265-0 http://dx.doi.org/10.1016/j.diabres.2017.03.036 DIAB 6955

To appear in:

Diabetes Research and Clinical Practice

Received Date: Revised Date: Accepted Date:

25 July 2016 14 February 2017 28 March 2017

Please cite this article as: M. Gradišer, M. Cigrovski Berković, I. Bilić-Ćurčić, Changes in HbA1c and hypoglycemic episodes in type 1 diabetes patients after switching to insulin glargine U300: pilot study, Diabetes Research and Clinical Practice (2017), doi: http://dx.doi.org/10.1016/j.diabres.2017.03.036

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1

Changes in HbA1c and hypoglycemic episodes in type 1 diabetes patients after switching to insulin glargine U300: pilot study Marina Gradišer1, Maja Cigrovski Berković2, Ines Bilić-Ćurčić3 1

Internal medicine ward, General hospital Čakovec, Čakovec, Croatia

2

Department for Endocrinology, Diabetes and Metabolism University Hospital Centre „Sestre

milosrdnice“, Zagreb, Croatia 3

Department of Pharmacology, Faculty of Medicine, University J.J.Strossmayer, Osijek,

Clinical, Hospital Center Osijek

Authors’ contributions MG, MBC and IBC conceived and designed this study, collected patients and drafted the manuscript.

Corresponding author Ines Bilic-Curcic, J. Huttlera 4, 31000 Osijek, Croatia Phone number: 00385-91-523-5970 Fax number: 0038531-511-733 e-mail: [email protected] Short running title: The effects of glargine U300 in diabetes type 1

2

Summary We included diabetes type 1 (T1DM) patients with suboptimal glycemic control on morning application glargine (I-Glar) U100, switching them to U300. After six months improvement in HbA1c was observed, while hypoglycemic episodes decreased. Switch from I-Glar U100 to U300 could be a good therapeutic option for that subset of patients. Key words: glargine U100, glargine U300, glycemic control, hypoglycemia, T1DM

3

Introduction Insulin therapy is essential for the treatment of type 1 diabetes (T1DM). However, due to pharmacological properties of insulin, it is often related to hypoglycemia, a major obstacle in reaching optimal glycemic targets in diabetic patients. Current research has shown that timing of insulin application can have an important effect on overall glucoregulation and in case of morning instead of evening application of basal insulin glargine U100 can reduce the hypoglycemic risk1. We reported recently that transition from bedtime to morning basal insulin (I-Glar U100) administration in poorly regulated type 1 diabetic patients could improve glucoregulation and reduce number of hypoglycemic episodes without affecting body weight2. However, those patients still remained suboptimally controlled. The new insulin glargine U300 (I-Glar U300) with flatter and more prolonged pharmacokinetic and pharmacodynamic profile than I-Glar U100 could represent a new, more efficient therapeutic option in this particular subset of patients 3. In present study we included those patients and investigated whether the transition to I-Glar U300 has a beneficiary effect on glucose regulation and hypoglycemic episodes.

Methods 18 patients (9 females and 9 male) with suboptimally controlled T1DM treated by intensified insulin regimen based on I-Glar U100 applied in the morning participated in this prospective longitudinal study. Written informed consent was obtained from each patient. This study complied with the Declaration of Helsinki and was approved by ethics committees of above mentioned institutions. Patients were eligible for participation if they were diagnosed with T1DM, had suboptimal glycemic control (HbA1c 7-8.1%) with hypoglycemic episodes. Hypoglycemia was defined

4

as measured BG values <3.9 mmol/L with or without symptoms of hypoglycemia, or unconfirmed hypoglycemia if symptoms were present but BG not checked at the time. In case where need of another person was required to treat hypoglycemia or it resulted in hospitalization it was regarded as serious. Patients were switched to I-Glar U300 morning application and initial dose was equal to pre switch basal insulin dose. Prior the transition of glargine administration there was a 12 week run in period where patients continued their usual insulin regimen and were encouraged to achieve optimal glycemic control. Basal insulin was titrated by the patient based on home self monitored glucose measurements (SMBG) according to the predefined pre-meal/fasting blood glucose of 4.4-6.7 mmol/L. Short-acting insulin analogue was titrated individually as necessary, aiming to reach a postprandial glucose of less than 7.8 mmol/L. Patients were also instructed to obtain 4-point and 8-point blood glucose values determined by SMBG prior to meals and snacks, occasionally postprandially, at bedtime, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic. In addition, frequency of hypoglycemic events was assessed using standard patient diaries. Frequent hypoglycemia was defined as approximately two to four times per week or more, nocturnal hypoglycemia applied to hypoglycemic events from bedtime to 06:00 am whereas morning hypoglycemia encompassed all events from 06:00 am till breakfast 4. HbA1c levels and lipid profile were determined and SMBG values were assessed as well as patient diaries at baseline (including data over a 12 week period prior screening phase), at the end of the 12 week screening period and 6 months after transition. All patients included at the screening phase maintained suboptimal regulation of diabetes with HbA1c ≥7%, continued to have nocturnal and/or morning hypoglycemic events and were therefore transitioned to morning application of I-Glar U300. The primary objective was to investigate changes in HbA1c values at the end point 6 months after the transition. Secondary

5

objective was to evaluate the effect of transition on incidence of hypoglycemia, insulin doses and weight.

Results Table 1 shows a comparison of the data obtained at baseline, at transition and 12 weeks after the transition. The average HbA1c was significantly reduced over time. Bonferroni correction for multiple comparison shows a significant reduction in the second measurement (at transition) compared to the first, and an additional significant reduction 6 months after introduction of I-Glar U300 than at transition. Regarding glycemic control based on SMBG values (4 point and 8 point), there was no statistically significant reduction in the average fasting BG values over time, however after Bonferroni correction for multiple comparisons fasting BG values were significantly lower after treatment with I-Glar U300 than at transition (Figure 1.). The average value of the pre lunch and pre dinner BG was significantly reduced over time. A significant reduction in the second relative to the first measurement for both values was present, as well as an additional significant reduction in the third measurement (Figure 1.). A total daily dose of I-Glar U300 remained unaffected when compared to pre-switch dose of I-Glar U100 as well as body weight and body mass index. Furthermore, a significant decrease in average morning hypoglycemic episodes per patient over time was observed. A significant reduction was present at transition point compared to baseline, with the additional significant reduction 6 months after treatment with I-Glar U300. Similarly, average number of nocturnal hypoglycemia per patient was significantly reduced over time, with a significant reduction at transition point compared to baseline, which is maintained 6 months after treatment with I-Glar U300, but with no additional decrease than at transition point. Due to small sample size, and due to the fact that some patients are prone to

6

more frequent hypoglycemic episodes, additional decrease in the number of hypoglycemia was verified with Excact test of Cochran’s Q test, measuring changes in the number of patients having hypoglycemia. Once again, statistically significant decrease in number of patients suffering from morning and nocturnal hypoglycemia was found (Table 1.). Additional benefits when switching to I-Glar U300 were noticed in lipid profile; the average value of total cholesterol and triglycerides was significantly reduced, while HDL-C statistically significantly increased over time.

Discussion According to our observation use of I-Glar U300 in young patients with T1DM, in whom tight glycemic control is suggested but failed mainly due to risk of hypoglycemia, would be a safe and successful treatment option. I-Glar U300 received a European marketing authorization in April 2015, so there are still very limited patient-oriented outcome data. Our present study adds to the ample of safety and efficacy evidence on I-Glar U300. In a randomized controlled trial (RCT) in 549 people with type 1 diabetes, I-Glar U300 had similar efficacy to insulin I-Glar U100 in terms of HbA1c reduction, and no benefit over IGlar U100 in terms of reduced hypoglycemic events 5. Unlike in the RCT, we observed additional HbA1c reduction in poorly controlled T1DM patients when switch was made from I-Glar U100 to I-Glar U300. Moreover, we noticed reduction in fasting BG after 6 month treatment with I-Glar U300 compared to I-Glar U100 as well as significant improvements in pre-lunch and pre-dinner BG levels. This might be associated with prolonged duration of action of I-Glar U300 and its improved pharmacokinetic and pharmacodynamic properties 3. Another issue from RCT is insulin I-Glar U300 dose, which according to data from RCT was reported higher compared to I-Glar U1005. On the contrary, our clinical data suggest that improvements in glucoregulation after switch to I-Glar U300 were not related to dose since

7

insulin dose remained unchanged. Unlike in RCT we did not register decrease in body mass or BMI with I-Glar U300 treatment. The most important benefit in this hypoglycemia-prone group of subjects was a decrease in hypoglycemic episodes. Since patients with recurrent hypoglycemia may be excluded from trials conducted for regulatory purposes it is not surprising that RCT data demonstrated no benefit of I-Glar U300 over I-Glar U100 in terms of reduced hypoglycemic events 5. This further emphasizes the importance of longer duration of action, flat profile and thus lower glucovariability leading to improved glycemic control and reduced hypoglycemias. However, observational nature of the study and the small number of subjects do not allow general conclusions. A large-scale, long-term clinical study is required for confirmation of the present results. We can conclude that insulin I-Glar U300 could be valuable therapeutic option in diabetes type 1 patient since it reduced number of hypoglycemic episodes, improved glycemic control while remaining body weight neutral with no change in insulin dose.

8

DISCLOSURE Marina Gradiser, Maja Cigrovski Berkovic and Ines Bilic-Curcic declare no conflict of interest.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study.

9

References 1. Hamann A, Matthaei S, Rosak C, et al. A randomized clinical trial comparing breakfast, dinner, or bedtime administration of insulin glargine in patients with type 1 diabetes. Diabetes Care. 2003;26(6):1738–44. 2. Gradiser M, Bilic-Curcic I, Djindjic B, et al. The Effects of Transition from Bedtime to Morning Glargine Administration in Patients with Poorly Regulated Type 1 Diabetes Mellitus: Croatian Pilot Study. Diabetes Ther 2015;6:643-648. 3. Becker RH, Nowotny I, Teichert L, et al. Low within- and between-day variability in exposure to new insulin glargine 300 U/ml. Diabetes Obes Metab. 2015 Mar;17(3):261-7. 4. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384-95. 5. Home PD, Bergenstal RM, Bolli GB, et al. New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes: A Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4). Diabetes Care. 2015;38(12):2217-25.

10

Figure 1. Average blood glucose (BG) values and Hba1c over follow up period. BG PP, postprandial blood glucose; BG, blood glucose; HbA1c glycated hemoglobin.

11

Table 1. Characteristics of the subjects at baseline, at transition and 6 months after the transition 6 months after

Baseline

At transition

HbA1c (%)

7.62 ± 0.43

7.45 ± 0.38*

6.90 ± 0.30†‡

Fasting BG (mmol/L)

6.16 ± 0.66

6.26 ± 0.30

6.07 ± 0.38†

Postprandial BG (mmol/L)

6.62 ± 0.66

6.55 ± 0.53

6.54 ± 0.32

Pre-lunch BG (mmol/L)

7.26 ± 0.62

6.82 ± 0.45*

6.48 ± 0.39†‡

Pre-dinner BG (mmol/L)

8.32 ± 0.52

6.88 ± 0.42*

6.57 ± 0.31†‡

BMI (kg/m2)

23.54 ± 3.19

23.53 ± 2.46

23.50 ± 2.37

Body weight (kg)

70.33 ± 15.21

70.10 ± 13.93

69.86 ± 13.85

Total cholesterol (mmol/L)

4.42 ± 0.45

4.30 ± 0.45

4.23 ± 0.40†‡

Triglycerides (mmol/L)

1.90 ± 0.45

1.67 ± 0.29*

1.63 ± 0.30‡

HDL (mmol/L)

1.00 ± 0.11

1.19 ± 0.08*

1.25 ± 0.08†‡

LDL (mmol/L)

3.20 ± 0.36

3.06 ± 0.44

3.11 ± 0.45

23.78 ± 6.13

24.67 ± 6.88

24.67 ± 6.88

12 weeks prior run in

12 weeks prior

6 months after

period

transition (run in period)

transition

1.89 ± 0.76

1.00 ± 1.14*

0.28 ± 0.46†‡

1.06 ± 0.73

0.28 ± 0.46*

0.06 ± 0.24‡

34

18

5

19

5

1

18

9

5‡

17

5

1‡

Daily dose of basal insulin (IU) Hypoglycemic episodes Average number of morning hypoglycemia per patient Average number of nocturnal hypoglycemia per patient Total number of morning hypoglycemia per period Total number of nocturnal hypoglycemia per period

transition

Number of patients with morning hypoglycemia per period§ Number of patients with nocturnal hypoglycemia per period§ Repeated measures ANOVA with Bonferroni correction for multiple correlation; HbA1c, glycated hemoglobin; BG, blood glucose; BMI, body mass index; *p<0.05 transition vs. baseline, †p<0.05 end point vs. transition; ‡p<0.05 reduction over time; §Cohran's Q Exact test