Original Article
`
`EFFECT OF GLARGINE INSULIN DELIVERY METHOD
`{PEN DEVICE VERSUS VIAL/SYRINGE)
`ON GLYCEMIC CONTROL AND
`PATIENT PREFERENCES IN PATIENTS
`WITH TYPE 1 AND TYPE 2 DIABETES
`
`Stacey A. Seggelke, RN, MS, CDE; R. Matthew Hawkins, PA-C; Joanna Gibbs, PA-C;
`Neda Rasouli, MD; Cecilia C. Low Wang, MD; Boris Draznin, MD, PhD
`
`ABSTRACT
`
`Objective: To evaluate the effects of two different
`glargine insulin delivery methods (pen device vs. vial/
`syringe) on glycemic control and patient preferences in a
`randomized, open-label, crossover, comparative effective(cid:173)
`ness study.
`Methods: Thirty-one patients discharged from the
`hospital were recruited for this study. In the hospital, all
`patients were treated with a basal-bolus insulin regimen.
`Upon discharge, 21 patients received glargine by pen
`device for 3 months and were then switched to vial/syringe
`for the next 3 months (group 1). Group 2 consisted of 10
`patients discharged on vial/syringe and converted to pen
`device after 3 months. Hemoglobin Ale (HbA 1) was mea(cid:173)
`sured at enrollment and at 3 and 6 months. A questionnaire
`assessing patient preference was administered at 3 and 6
`months.
`Results: Groups 1 and 2 had similar baseline HbA1c
`(10.7 ± 2.2% and 11.2 ± 2.5%, respectively) and similar
`reduction in HbA1c at 3 months (7.8 ± 1.7% and 7.3 ±
`1.4%, respectively; P<.001 vs. baseline). However, after
`crossover, the changes in HbA1c from 3 to 6 months were
`significantly different between groups. HbA1c increased
`to 8.5 ± 2.0% at 6 months in group 1 after switching to
`the vial/syringe but remained unchanged (7.1 ± 1.6%) in
`group 2 after switching to a pen device (P<.01, group 1
`
`Submitted for publication September 27, 2013
`Accepted for publication November 19, 2013
`From the University of Colorado Anschutz Medical Center, Aurora,
`Colorado.
`Address correspondence to Dr. Boris Draznin, Mail Stop 8106, 12801 E 17th
`Avenue, Aurora, CO 80045.Email:boris.draznin@ucdenver.edu.
`Published as a Rapid Electronic Article in Press at http:/ /www.endocrine
`practice.org on December 10, 2013. DOl:10.4158/EP13404.OR
`To purchase reprints of this article, please visit: www.aace.com/reprints.
`Copyright© 2014 AACE.
`
`vs. group 2). Patient questionnaires after each phase of the
`trial revealed that patients found the pen device more con(cid:173)
`venient and were more likely to recommend this insulin
`delivery method to someone else.
`Conclusion: Patients switching to aglarginependevice
`achieved lower HbA1c at the 6-month follow-up. Patients
`in both groups overwhelmingly preferred glargine pens
`over vials/syringes. (Endocr Pract. 2014;20:536-539)
`
`Abbreviation:
`HbA1c = hemoglobin A 1c
`
`INTRODUCTION
`
`A number of well-designed studies have demonstrated
`both the accuracy and convenience of insulin pen devices
`for treatment of type 1 and type 2 diabetes (1-5). Prefilled
`and disposable pens are now being used widely around
`the world by patients with diabetes on insulin treatment.
`However, due to both perceived and sometimes actual
`higher costs associated with use of insulin pens relative to
`the traditional vial/syringe method, many institutions and
`insurance plans often disincentivize the use of pen devices
`by their patients. Real or perceived cost issues deprive
`many uninsured and underinsured patients with diabetes
`of the opportunity to use a more convenient and possibly
`more efficacious device for administration of insulin (4).
`The key question is whether insulin pen devices pro(cid:173)
`vide a therapeutic advantage over the vial/syringe method
`of insulin delivery, particularly among patients at higher
`risk for poor glycemic control and diabetes complications.
`Therefore, we conducted a crossover study among indigent
`and Medicaid-covered patients with type 1 or type 2 diabe(cid:173)
`tes who were discharged from the University of Colorado
`Hospital on a basal-bolus insulin regimen. The aim of this
`study was to evaluate the effects of two different glargine
`insulin delivery methods (pen device and vial/syringe) on
`glycemic control and patient preference in indigent patients
`with type 1 or type 2 diabetes with poor glycemic control.
`
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`
`536 ENDOCRINE PRACTICE Vol 20 No. 6 June 2014
`
`Copyright© 2014 AACE
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`Glargine Pen Versus Vial/Syringe, Endocr Pract. 2014;20(No. 6) 537
`
`METHODS
`
`This was a randomized, open-label study with a cross(cid:173)
`over design, a real-life comparative effectiveness trial. We
`recruited 41 patients with type 1 and type 2 diabetes, either
`indigent or receiving Medicaid, who were discharged from
`the hospital on a basal-bolus insulin regimen (glargine
`and humalog). Twenty-three subjects were randomized to
`group 1 and received glargine by pen device for 3 months
`and were then switched to vial/syringe for the next 3
`months. Eighteen subjects were randomized to group 2
`and received glargine insulin via vial/syringe for the first 3
`months and then by pen device for an additional 3 months.
`Randomization was performed using odd-even last digit
`medical record numbers. Patients whose medical record
`number ended with an odd numeral were randomized into
`group 1, whereas those whose record number ended with
`an even numeral were randomized into group 2. None of
`the patients in either group had been exposed to any pen
`device before this study. The study design is outlined in
`Figure 1.
`Two subjects in group 1 and 8 subjects in group 2 were
`lost to follow-up at 3 or 6 months and were excluded from
`the final analysis. Thirty-one subjects completed the study:
`21 in group 1 and 10 in group 2.
`Hemoglobin Ale (HbA1J was measured at enrollment
`and at 3 and 6 months using the same assay. A question(cid:173)
`naire assessing patient preferences was administered at 3
`months (the end of the initial treatment period) and at 6
`months (at the end of the crossover period). The unvali(cid:173)
`dated questionnaire consisted of 3 questions, with a satis(cid:173)
`faction scale ranging from O (very dissatisfied) to 6 (very
`satisfied):
`Q 1: How satisfied are you with your current treatment?
`Q2: Would you recommend this form of treatment to
`others?
`Q3: How satisfied would you be to continue your pres(cid:173)
`ent form of treatment?
`
`Vial-Syringe
`
`Hospital
`discharge
`
`HbAlc at 0
`
`3mo
`
`6mo
`
`Fig. 1. Crossover study design for group 1 (X) and group 2 ( • ).
`
`Questionnaire results from all subjects in each group
`were combined for each treatment modality in the final
`analysis. The numerical scores of the answers (0 to 6) were
`tabulated and the mean ± SEM were compared using the
`Student's t test.
`All subjects self-administered insulin lispro by vial/
`syringe throughout the study. All study medications were
`provided to subjects free of charge. Pen devices were given
`to group 1 upon discharge from the hospital and to group
`2 at the 3-month follow-up visit by one of the authors.
`Instruction on how to use the pen device was provided at
`the same time. Insulin lispro adjustments were made at
`the 3-month follow-up visit as well. Compliance with the
`prescribed insulin regimen was evaluated at each visit by
`reviewing the insulin administration log and meter down(cid:173)
`load. The study was approved by the Colorado Multiple
`Institutional Review Board prior to any study procedures
`being performed.
`
`RESULTS
`
`The characteristics of the 31 subjects who enrolled and
`completed this study are shown in Table 1. The average age
`of subjects was 49 ± 11 years in group 1 and 46 ± 15 years
`in group 2 (not significant). There were 3 subjects with
`type 1 diabetes in each group, and the gender and ethnic
`distributions were similar.
`One of the most revealing observations was the high
`drop-out rate, despite receipt of free long-acting insu(cid:173)
`lin supplies for 6 months. A total of 10 subjects (24.4%)
`dropped out, including 2 subjects in group 1 (8.7%) and
`8 in group 2 (44.4%). There were no differences in edu(cid:173)
`cation, socioeconomic, or demographic characteristics
`between the dropouts and nondropouts, nor were there
`any differences between groups with respect to the clinical
`course of diabetes or any other comorbidity. Because of
`
`Table 1
`Clinical Characteristics of
`Patients Enrolled in the Studya
`
`Group 1
`(n = 21)
`49.3 ± 10.8
`
`Group 2
`(n = 10)
`46.2 ± 14.9
`
`Age (years)
`Mean± SD
`6/4
`13/8
`Men/Women
`6
`11
`Caucasian
`3
`5
`Hispanic
`1
`5
`African American
`3
`3
`Type 1 diabetes
`7
`18
`Type 2 diabetes
`3 There were no statistically significant differences between
`the groups in any of the parameters presented.
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`538 Glargine Pen Versus Vial/Syringe, Endocr Pract. 2014;20(No. 6)
`
`Copyright© 2014 AACE
`
`the small absolute number of patients, the difference in the
`dropout rate was not significant between the groups.
`A second important observation is that subjects
`who completed all study procedures and were compli(cid:173)
`ant with their study medications demonstrated dramati(cid:173)
`cally improved metabolic control, regardless of the mode
`of insulin administration (Fig. 2). The HbA1c in group 1
`dropped from 10.7 ± 2.2% to 7.8 ± 1.7% at 3 months and
`from 11.2 ± 2.5% to 7.3 ± 1.4% in group 2 (P<.001 between
`baseline and 3 months for both groups). Neither the basal
`nor 3-month HbA1c were statistically different between the
`groups. However, following the crossover period, subjects
`using the pen device remained in better control (group 2
`HbA1c, 7.1 ± 1.6%) than the subjects who switched to vial/
`syringe (group 1 HbA1c, 8.5 ± 2.0%; P<.01).
`The results of the patient satisfaction questionnaire
`are summarized in Table 2. Subjects using the pen device
`clearly preferred this mode of insulin administration,
`reporting a significantly higher level of satisfaction for all
`3 questions (P<.0001 compared with vial/syringe use).
`
`DISCUSSION
`
`In general, adherence to chronic drug regimens,
`including those for diabetes management, is frequently
`inadequate (6-9). Furthermore, lower socioeconomic sta(cid:173)
`tus is associated with greater barriers to adherence with
`therapeutic regimens (7). Most of the studies using objec(cid:173)
`tive measures of medication adherence (as opposed to
`self-reported adherence) support its association with better
`glycemic control in patients with diabetes (7,9,10-13). Our
`results support this notion as well. Adherence to glargine
`insulin administration as prescribed (review of insu(cid:173)
`lin administration log and meter downloads by the staff)
`greatly improved metabolic control in indigent patients in
`our study, regardless of the mode of administration. HbA1c
`
`13
`
`7
`
`.............. i~-·-·-·-·J}
`
`P<0.01
`
`*
`
`0
`
`3mo
`
`Gmo
`
`Fig. 2. Hemoglobin Ale at the initiation of the study and at 3 and
`6 months in group 1 (X) and group 2 ( • ). * P<.001 versus initial
`values.
`
`was reduced robustly and precipitously (Fig. 2). We did
`not evaluate potential reasons for previous poor compli(cid:173)
`ance, but the results from this study clearly show that com(cid:173)
`pliance with a prescribed insulin regimen is critical for
`improvement in metabolic control.
`The dropout rate in our study (24.4%) is certainly
`disturbing. The 10 subjects who dropped out made up a
`quarter of those initially emolled and were lost to follow(cid:173)
`up even when given glargine insulin at no financial cost.
`This is likely to represent a behavioral barrier to medica(cid:173)
`tion adherence, although a financial component (e.g., the
`cost of transportation) cannot be ruled out. Further stud(cid:173)
`ies are needed to understand the causes of nonadherence
`and dropout. Interestingly, there were more subjects who
`dropped out during the vial/syringe phase than among
`patients in the pen-device phase.
`After the crossover phase, subjects using pen devices
`maintained good metabolic control, whereas those switch(cid:173)
`ing to the vial/syringe mode of glargine administration
`
`Table 2
`Questionnaire Results 3
`
`SoloSTAR Vial/syringe
`(n = 31)
`(n = 31)
`5.5 ± 0.6
`3.1±0.6
`
`5.4 ± 0.4
`
`3.0± 0.9
`
`How satisfied are
`you with your current
`treatment?
`Would you recommend
`this form of treatment to
`others?
`How satisfied would
`you be to continue
`your present form of
`treatment?
`a Answer scale: 6 = " very satisfied;" 0 = "very dissatisfied."
`
`5.8 ± 0.4
`
`2.7 ± 0.7
`
`P value
`
`<.0001
`
`<.0001
`
`<.0001
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`Glargine Pen Versus Vial/Syringe, Endocr Pract. 2014;20(No. 6) 539
`
`drifted to a higher HbA1c (P<.001 between the 2 groups).
`Subject satisfaction with treatment after switching to the
`vial/syringe mode also dropped significantly.
`Recently, Grabner et al (14) examined clinical and
`economic outcomes among patients with diabetes using a
`glargine pen versus those using a vial/syringe in a large
`retrospective administrative claim study. Following initia(cid:173)
`tion of glargine therapy, patients using a pen device were
`more adherent to their medication (P<.001) and had lower
`HbA1c during follow-up (P<.001) compared with patients
`using a vial/syringe. Similarly, Davis et al (15) observed
`that among 3,842 patients with type 2 diabetes (n = 1,921
`per group), those who initiated glargine therapy with a
`disposable pen showed better treatment persistence and
`less hypoglycemia in comparison with those using a vial/
`synnge.
`The results of our crossover study among indigent and
`Medicaid-covered patients with type 1 or type 2 diabetes
`are consistent with many previous assessments of patient
`preference in favor of pen devices (1-5). The use of dispos(cid:173)
`able pens for administration of insulin in Europe, Canada,
`and Australia was accompanied by higher efficacy, adher(cid:173)
`ence to therapy, and patient satisfaction (4,16). It appears
`that the use of pen devices might actually lower the over(cid:173)
`all treatment cost as a consequence of better control and
`higher treatment adherence rates (17,18).
`
`CONCLUSION
`
`In conclusion, our data from a high-risk, transitional
`population of patients crossing over from one form of insu(cid:173)
`lin glargine delivery to another strongly suggest that both
`metabolic control and patient preference are significantly
`improved in patients using disposable pens as compared
`with those using vials/syringes. These data support more
`widespread use of pen devices for insulin administration to
`improve medication adherence and glycemic control.
`
`ACKNOWLEDGMENT
`
`This study was supported by Sanofi and the Foundation
`for Biomedical Education and Research.
`
`DISCLOSURE
`
`The authors have no multiplicity of interest to disclose.
`
`REFERENCES
`
`1. Korytkowski M, Bell D, Jacobsen C, Suwannasari R.
`A multicenter, randomized, open-label, comparative, two(cid:173)
`period crossover trial of preference, efficacy, and safety
`profiles of a prefilled, disposable pen and conventional vial/
`syringe for insulin injection in patients with type 1 or 2 dia(cid:173)
`betes mellitus. Clin Ther. 2003;25:2836-2848.
`2. Rubin RR, Peyrot M. Quality of life, treatment satisfac(cid:173)
`tion, and treatment preference associated with use of a pen
`
`device delivering a premixed 70/30 insulin aspart suspen(cid:173)
`sion (aspart protamine suspension/soluble aspart) versus
`alternative treatment strategies. Diabetes Care. 2004;27:
`2495-2497.
`3. Schwartz S, Vlajnic A. Validation of the SoloSTAR insu(cid:173)
`lin pen. Diabetes Technol Ther. 2008;10:351-357.
`4. Hancu N, Czupryniak L, Genestin E, Sourij H. A pan(cid:173)
`European and Canadian prospective survey to evaluate
`patient satisfaction with the SoloSTAR insulin injection
`device in typel and type 2 diabetes. J Diabetes Sci Technol.
`2011;5: 1224-1234.
`5. Toscano D, Brice J, Alfaro C. Usage and perception of
`pen injectors for diabetes management: a survey of type
`2 diabetes patients in the United States. J Diabetes Sci
`Technol. 2012;6:686-694.
`6. Haynes RB, McKibbob KA, Kanani R. Systematic
`review of randomised trials of interventions to assist
`patients to follow prescriptions for medications. Lancet.
`1996;348:383-386.
`7. Schectman J, Nadkarni MM, Voss JD. The association
`between diabetes metabolic control and drug adherence in
`an indigent population. Diabetes Care. 2002;25: 1015-1021.
`8. Cramer JA. A systematic review of adherence with medi(cid:173)
`cations for diabetes. Diabetes Care. 2004;27: 1218-1224.
`9. Aikens JE, Piette JD. Longitudinal association between
`medication adherence and glycaemic control in Type 2 dia(cid:173)
`betes. Diabet Med. 2013;30:338-344.
`10. Diel AK, Bauer RL, Sugarek NJ. Correlates of medica(cid:173)
`tion compliance in non-insulin-dependent diabetes melli(cid:173)
`tus. South Med J. 1987;80:332-335.
`11. Chousa FP, Gullen VFG, Otero MD, Beltran DO, Lopez
`RP, Sanchez JM. Usefulness of six indirect methods to
`evaluate drug therapy compliance in non insulin depen(cid:173)
`dent diabetes mellitus. Revista Clinica Espanola. 1997;
`197:555-559.
`12. Peterson GM, McLean S, Senator GB. Determinants of
`patient compliance, control, presence of complications,
`and handicap in non-insulin-dependent diabetes. Aust NZ J
`Med. 1984;14:135-141.
`13. Cohen HW, Shmukler C, Ullman R, Rivera CM,
`Walker EA. Measurements of medication adherence in
`diabetic patients with poorly controlled HbA(lc). Diabet
`Med. 2010;27:210-216.
`14. Grabner M, Chu J, Raparla S, Quimbo R, Zhou S,
`Conoshenti J. Clinical and economic outcomes among
`patients with diabetes mellitus initiating insulin glargine
`pen versus vial. Postgrad Med. 2013;125:204-213.
`15. Davis SN, Wei W, Garg S. Clinical impact of initiating
`insulin glargine therapy with disposable pen versus vial in
`patients with type 2 diabetes mellitus in a managed care set(cid:173)
`ting. Endocr Pract. 2011;17:845-852.
`16. Carter J, Roberts A. Usability of a pre-filled insulin injec(cid:173)
`tion device in a 3-month observational survey of everyday
`clinical practice in Australia. Curr Med Res Opin. 2008;24:
`2741-2749.
`17. Lee WC, Balu S, Cobden D, Joshi AV, Pashos CL.
`Medication adherence and the associated health-economic
`impact among patients with type 2 diabetes mellitus con(cid:173)
`verting to insulin pen therapy: an analysis of third-party
`managed care claims data. Clin Ther. 2006;28: 1701-1725.
`18. Pawaskar MD, Camacho FT, Anderson RT, Cobden D,
`Joshi AV, Balkrishnan R. Health care cost and medication
`adherence associated with initiation of insulin pen therapy
`in Medicaid-enrolled patients with type 2 diabetes: a retro(cid:173)
`spective database analysis. Clin Ther. 2007;29: 1294-1305.
`
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