Journal of Clinical & Translational Endocrinology 15 (2019) 35–36
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`Contents lists available at ScienceDirect
`Journal of Clinical & Translational Endocrinology
`
`journal homepage: www.elsevier.com/locate/jcte
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`Twice-daily insulin glargine for patients with uncontrolled type 2 diabetes mellitus
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`T
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`A R T I C L E I N F O
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`Keywords:
`Insulin glargine
`Type 2 diabetes
`Uncontrolled glucose
`
`Insulin glargine is recombinant human insulin analog that is com-
`monly used in patients with type 2 diabetes as well as those with type 1
`diabetes. Pharmacokinetic and pharmacodynamics studies of insulin
`glargine had shown that it has an onset of action that ranged from 1.2 to
`1.8 h while its duration of action is 18 to 26 h [1]. Because of its long
`duration of action insulin glargine is usually prescribed once daily.
`However, several reports have shown that the administration of insulin
`glargine once daily is not enough to achieve adequate glucose control in
`some patients requiring a twice daily dosing [2–9]. The first report on
`using insulin glargine twice daily was published shortly after its
`availability [2]. It described a patient with type 1diabetes who had
`consistently elevated bedtime glucose values on once daily insulin
`glargine administered in the evening. There was significant improve-
`ment in glucose values after changing the frequency of insulin glargine
`to twice daily as a split dose every 12 h. Albright and colleagues found
`that twice daily glargine therapy was required in patients with type 1
`diabetes who developed morning hypoglycemia and/or afternoon hy-
`perglycemia while on once daily therapy [3]; the twice daily regimen
`was associated with a significant reduction in HbA1c levels compared to
`patients who were on once daily therapy.
`Objectives
`We aimed to examine changes in glucose control in a cohort of
`patients with type 2 diabetes after switching from once daily to twice
`daily insulin glargine U-100 due to uncontrolled glucose levels. The
`reason for switching from once to twice daily insulin glargine therapy
`was the limited ability to titrate insulin glargine doses at bedtime be-
`cause of morning hypoglycemia (early morning or before breakfast)
`and/or persistent hyperglycemia before dinner despite titrating meal
`insulin doses at lunch.
`Methods
`Patients were required to be on basal/meal insulin regimen for at
`least 6 months to be enrolled. We also investigated potential specific
`characteristics that can predict the need for twice daily administration
`of insulin glargine. The study protocol was approved by Hamad medical
`corporation institutional review board. Data on patient characteristics
`including demographics, duration of diabetes, weight, body mass index,
`
`doses of insulin glargine and meal insulin, and use of non-insulin glu-
`cose-lowering medications were collected while on once daily and after
`the switch to twice daily glargine therapy. Secondary analysis eval-
`uated the potential predictors for the use of twice daily insulin glargine
`including body weight, body mass index, duration of diabetes, HbA1c
`levels, insulin glargine dose and meal insulin dose. This was undertaken
`by comparing the twice daily glargine group to a matched cohort of 210
`patients with type 2 diabetes who were on basal/meal insulin regimen
`that included once daily insulin glargine administered at bedtime. All
`statistical analyses were performed using Statistical Package for Social
`Sciences (SPSS) version 22. Descriptive and inferential statistics were
`used to characterize the study sample and test hypotheses. Paired
`sample t-test was used to assess the primary objective of the study
`which was to identify a difference in HbA1c levels when insulin glargine
`is switched from once daily to twice daily. Bi-variate analysis was
`performed using independent sample t-test or Mann Whitney U test
`whenever appropriate to compare quantitative variables between those
`who were on insulin glargine once daily to those who were on twice
`daily therapy. Qualitative variables between the two groups were
`compared using Pearson Chi-square test or Fisher exact test as appro-
`priate. Multiple logistic regression model was used to identify sig-
`nificant independent factors associated with the use of twice daily in-
`sulin glargine therapy after adjusting for potentially confounding
`factors. The Wald test was computed on each predictor to determine
`which were significant. Adjusted odds ratio and 95% confidence in-
`terval for the adjusted odds ratio were reported. A “P” value < 0.05
`(two tailed) was considered statistically significant.
`Results
`A total number of 50 patients on twice daily insulin glargine were
`included. Men formed 58% of
`the
`cohort; mean age was
`55.3 ± 8.2 years; mean duration of diabetes was 17.6 ± 8.2 years;
`mean body mass index was 32.8 ± 5.5; mean follow up period was
`8.2 ± 2.1 months. Mean HbA1c
`decreased
`significantly
`from
`10.3 ± 1.5% (89.1 ± 8.5 mmol/mol) while on once daily insulin
`glargine to 8.4 ± 1.3% (68.3 ± 8.3 mmol/mol) on twice daily
`therapy, P < 0.001. Mean daily insulin glargine dose increased from
`53 ± 20.9 units to 77.8 ± 29.4 units while on once and twice daily
`glargine therapy respectively, P < 0.001. Conversion from once to
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`https://doi.org/10.1016/j.jcte.2018.12.002
`Received 12 November 2018; Received in revised form 6 December 2018; Accepted 6 December 2018
`2214-6237/ © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
`(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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`Mylan Ex.1059
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`Weight (kg)
`Glargine dose (units/day)
`Meal insulin dose (units/day)
`HbA1C % [mmol/mol]
`
`0.002
`< 0.001
`< 0.001
`< 0.001
`
`Table 1
`Changes in clinical parameters on switching from once-daily to twice-daily
`insulin glargine therapy.
`Factors
`
`P-Value
`
`Group (n = 50)
`On twice-daily
`On once-daily
`Glargine
`Glargine
`89.4 ± 16.2
`87.4 ± 15.9
`77.8 ± 29.4
`53 ± 20.9
`59.2 ± 50.2
`38.7 ± 38.6
`8.4 ± 1.3
`10.3 ± 1.5
`[68.3 ± 8.3]
`[89.1 ± 8.5]
`*Results are expressed as mean ± standard deviation.
`twice daily dosing resulted in a significant increase in the mean total
`daily insulin dose from 91.7 ± 45.5 to 138.3 ± 69.9 units, P < 0.01.
`Table 1 shows the changes in several parameters when patients were
`switched from once to twice daily insulin glargine therapy. There was
`no change in the use of other glucose-lowering medications or their
`doses after the switch to twice daily glargine therapy. In the secondary
`analysis using multivariate logistic regression revealed that HbA1c level
`(adjusted odds ratio 1.65, 95% CI 1.3–2.0, P < 0.01) and insulin
`glargine dose (adjusted odds ratio 1.35, 95% CI 1.2–1.5, P < 0.001)
`were independent predictors of twice daily therapy.
`Discussion
`This study demonstrated that the use of twice daily insulin glargine
`U-100 in patients with uncontrolled type 2 diabetes on basal/meal re-
`gimen significantly improved glucose control. The main reason that
`limited the titration of insulin doses when these patients were on once
`daily glargine is the occurrence of morning hypoglycemia and/or per-
`sistent hyperglycemia before dinner despite titrating meal insulin doses
`at lunch. Data on the use of twice daily glargine therapy is limited and
`involved mainly patients with type 1 diabetes [2–9]. The largest study
`that examined this issue involved 82 patients with type 1 diabetes [3];
`the protocol recommended changing the dosing of insulin glargine to
`twice daily if HbA1c levels remained high and/or if glucose levels were
`persistently high before dinner despite titration of the dose of meal
`insulin at lunch. The investigators found that 24% of patients required
`the use of glargine twice daily which resulted in a significant im-
`provement in HbA1c levels. Improvement in glucose profile was de-
`monstrated in other reports that included smaller number of patients
`with type 1 diabetes [4–6]. These results were not replicated in two
`other studies: Garg and colleagues found no difference in glucose
`control and the incidence of hypoglycemia in a cohort of 104 patients
`with type 1 diabetes on twice daily insulin glargine compared to 161
`patients on once daily glargine [7]. Burge et al found no difference in
`serum insulin and glucose levels in 10 patients with type 1 diabetes
`after the administration of equivalent daily doses of insulin glargine
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`Journal of Clinical & Translational Endocrinology 15 (2019) 35–36
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`injected once or twice daily during a 38-hour fast [8]. We found only
`one published study on the use of twice daily insulin glargine in pa-
`tients with type 2 diabetes [9]. In this study, the investigators evaluated
`18 patients with type 2 diabetes who were on twice daily insulin
`glargine and compared them to 117 patients on once daily therapy. The
`authors reported improvement in glucose control in patients on twice
`daily therapy and found that the dose of glargine was the main pre-
`dictor for switching to twice daily regimen. Our findings, with a larger
`number of patients, represent the second study of twice daily insulin
`glargine therapy in patients with type 2 diabetes and confirm the effi-
`cacy of this regimen.
`In conclusion, twice daily insulin glargine results in a significant
`improvement in glucose control in selected patients with type 2 dia-
`betes. We suggest to consider this regimen for patients who continue to
`have uncontrolled glucose on basal/meal insulin regimen particularly if
`they are on high doses of insulin glargine. Prospective randomized
`controlled trials should help confirm these findings and define patient
`groups who will benefit from twice daily insulin glargine therapy.
`References
`
`[1] Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, et al.
`Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting
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`[2] Clement S, Bowen-Wright H. Twenty-four hour action of insulin glargine (Lantus)
`may be too short for once-daily dosing: a case report. Diabetes Care
`2002;25:1479–80.
`[3] Albright ES, Desmond R, Bell DS. Efficacy of conversion from bedtime NPH insulin
`injection to once- or twice-daily injections of insulin glargine in type 1 diabetic pa-
`tients using basal/bolus therapy. Diabetes Care 2004;27:632–3.
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`[5] Youssef D, El Abbassi A, Woodby G, Peiris AN. Benefits of twice-daily injection with
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`[6] Hopkinson HE, Jacques RM, Gardner KJ, Amiel SA, Mansell P. Twice-rather than
`once-daily basal insulin is associated with better glycaemic control in Type 1 diabetes
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`ment. Diabet Med 2015;32:1071–6.
`[7] Garg SK, Gottlieb PA, Hisatomi ME, D'Souza A, Walker AJ, Izuora KE, et al. Improved
`glycemic control without an increase in severe hypoglycemic episodes in intensively
`treated patients with type 1 diabetes receiving morning, evening, or split dose insulin
`glargine. Diabetes Res Clin Pract 2004;66:49–56.
`[8] Burge M, Schroeder E, Mitchell S. Assessing insulin effectiveness at the end of the
`day: once-daily versus twice-daily insulin glargine injection. J Diabetes Mellitus
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`[9] Housel AK, Shaw RF, Waterbury NV. Glucose control in patients with type 2 diabetes
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`2010;88:e17–9.
`Mohsen Eledrisi⁎, Noor Nabeel Suleiman, Obada Salameh,
`Mohammad Khair Hamad, Omar Rabadi, Ahmed Mohamed,
`Rana Al Adawi, Abdul Salam
`Department of Medicine, Hamad Medical Corporation, Doha, Qatar
`E-mail address: meledrisi@hamad.qa (M. Eledrisi).
`
`⁎ Corresponding author at: Department of Medicine, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
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`Mylan Ex.1059
`Mylan v. Sanofi - IPR2018-01675
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