10
Review Assessment of Patient-Reported Outcomes of Insulin Pen Devices Versus Conventional Vial and Syringe Cliff Molife, M.P.H., 1 Lauren J. Lee, Pharm.D., M.S., 1 Lizheng Shi, Ms.Pharm., Ph.D., 2 Monika Sawhney, M.S.W., 2 and Sheila M. Lenox, R.D., M.S., C.D.E. 1 Abstract Patient-reported outcomes (PROs) associated with insulin therapy are potentially important determinants of adherence to diabetes management programs. This article reviews published evidence of PROs over the past 3 decades in patients with type 1 diabetes (T1D) and=or type 2 diabetes (T2D) who used vial and syringe for insulin delivery compared to those who used insulin pens. Based on predetermined selection criteria, articles were identified through a search of primary sources published from January 1980 to February 2008. Two independent reviewers determined study eligibility and performed a detailed evaluation of the articles that met the selection criteria. Of the 124 articles screened, 41 met selection criteria. Approximately 75% of the selected articles were published between 1990 and 2008, and a majority (78%) of the research studies was conducted outside the United States. Most (>75%) of the studies evaluated male and female patients with T1D and=or T2D and mean ages around 45 years. Studies used varied comparative study designs with follow-up periods ranging from 2 weeks to 5 years. The PROs assessed in these articles included preference, acceptability, treatment satisfaction, ease of use, convenience, injection pain, handling, and dosing. Most articles (n ¼ 36) showed more favorable PROs for insulin pen users compared to vial and syringe users. These findings have potential clinical and policy implications for patients, diabetes care providers, and=or payers to make evidence-based decisions regarding ways to facilitate initiation and management of insulin therapy. Introduction O ptimal diabetes management through improved glycemic control has been shown to reduce the risk of developing diabetes-related microvascular complications. 1,2 Evidence supports that direct medical costs associated with treatment of type 2 diabetes (T2D) are significantly higher for persons who have poor glycemic control as compared to those who have optimal glycemic control. 3 It is estimated that the majority of patients with T2D do not achieve optimal glycemic control (e.g., glycosylated hemoglobin <7%, as re- commended by the American Diabetes Association). 4,5 Mul- tiple daily insulin injections are often recommended by healthcare providers to improve glycemic control. Increased treatment burden for patients on multiple daily insulin injections may occur when using vial and syringe. Non- adherence to insulin treatment, due to factors related to in- jection therapy, is a potential contributing factor for the suboptimal diabetes management trend. 5,6 In certain studies, the use of vial and syringes has been reported to be cumber- some and inconvenient, and for some patients, it was socially stigmatizing or fear inducing. 7 Patient self-management is a critical factor in achieving optimal diabetes management. 4 Some self-management or therapy effects are known only to the patient (e.g., injection pain); hence, perspectives of patients on related outcomes and burden of self-management are critical to investigate. Nu- merous studies have examined patient preference and other patient-reported outcomes (PROs) associated with the use of various insulin delivery devices. Reviews of these studies have consistently concluded that among patients with dia- betes, an overall greater preference and acceptance for insulin pen devices exist compared to conventional vial and sy- ringe. 8–13 However, these reviews were conducted with a focus on specific insulin pen devices (e.g., NovoPen Ò [Novo Nordisk A=S, Copenhagen, Denmark]). The objective of this review was to conduct a comprehensive systematic litera- ture search and report the comparative PRO data between all 1 Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indianapolis. 2 Tulane University, Health Systems Management, New Orleans, Louisiana. DIABETES TECHNOLOGY & THERAPEUTICS Volume 11, Number 8, 2009 ª Mary Ann Liebert, Inc. DOI: 10.1089=dia.2009.0007 529

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Page 1: Assessment of Patient-Reported Outcomes of Insulin Pen Devices Versus Conventional Vial and Syringe

Review

Assessment of Patient-Reported Outcomes of InsulinPen Devices Versus Conventional Vial and Syringe

Cliff Molife, M.P.H.,1 Lauren J. Lee, Pharm.D., M.S.,1 Lizheng Shi, Ms.Pharm., Ph.D.,2

Monika Sawhney, M.S.W.,2 and Sheila M. Lenox, R.D., M.S., C.D.E.1

Abstract

Patient-reported outcomes (PROs) associated with insulin therapy are potentially important determinants ofadherence to diabetes management programs. This article reviews published evidence of PROs over the past 3decades in patients with type 1 diabetes (T1D) and=or type 2 diabetes (T2D) who used vial and syringe forinsulin delivery compared to those who used insulin pens. Based on predetermined selection criteria, articleswere identified through a search of primary sources published from January 1980 to February 2008. Twoindependent reviewers determined study eligibility and performed a detailed evaluation of the articles that metthe selection criteria. Of the 124 articles screened, 41 met selection criteria. Approximately 75% of the selectedarticles were published between 1990 and 2008, and a majority (78%) of the research studies was conductedoutside the United States. Most (>75%) of the studies evaluated male and female patients with T1D and=or T2Dand mean ages around 45 years. Studies used varied comparative study designs with follow-up periods rangingfrom 2 weeks to 5 years. The PROs assessed in these articles included preference, acceptability, treatmentsatisfaction, ease of use, convenience, injection pain, handling, and dosing. Most articles (n¼ 36) showed morefavorable PROs for insulin pen users compared to vial and syringe users. These findings have potential clinicaland policy implications for patients, diabetes care providers, and=or payers to make evidence-based decisionsregarding ways to facilitate initiation and management of insulin therapy.

Introduction

Optimal diabetes management through improvedglycemic control has been shown to reduce the risk of

developing diabetes-related microvascular complications.1,2

Evidence supports that direct medical costs associated withtreatment of type 2 diabetes (T2D) are significantly higherfor persons who have poor glycemic control as compared tothose who have optimal glycemic control.3 It is estimated thatthe majority of patients with T2D do not achieve optimalglycemic control (e.g., glycosylated hemoglobin <7%, as re-commended by the American Diabetes Association).4,5 Mul-tiple daily insulin injections are often recommended byhealthcare providers to improve glycemic control. Increasedtreatment burden for patients on multiple daily insulininjections may occur when using vial and syringe. Non-adherence to insulin treatment, due to factors related to in-jection therapy, is a potential contributing factor for thesuboptimal diabetes management trend.5,6 In certain studies,

the use of vial and syringes has been reported to be cumber-some and inconvenient, and for some patients, it was sociallystigmatizing or fear inducing.7

Patient self-management is a critical factor in achievingoptimal diabetes management.4 Some self-management ortherapy effects are known only to the patient (e.g., injectionpain); hence, perspectives of patients on related outcomes andburden of self-management are critical to investigate. Nu-merous studies have examined patient preference and otherpatient-reported outcomes (PROs) associated with the use ofvarious insulin delivery devices. Reviews of these studieshave consistently concluded that among patients with dia-betes, an overall greater preference and acceptance for insulinpen devices exist compared to conventional vial and sy-ringe.8–13 However, these reviews were conducted with afocus on specific insulin pen devices (e.g., NovoPen� [NovoNordisk A=S, Copenhagen, Denmark]). The objective of thisreview was to conduct a comprehensive systematic litera-ture search and report the comparative PRO data between all

1Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indianapolis.2Tulane University, Health Systems Management, New Orleans, Louisiana.

DIABETES TECHNOLOGY & THERAPEUTICSVolume 11, Number 8, 2009ª Mary Ann Liebert, Inc.DOI: 10.1089=dia.2009.0007

529

Page 2: Assessment of Patient-Reported Outcomes of Insulin Pen Devices Versus Conventional Vial and Syringe

insulin pen devices and conventional vial and syringe in di-abetes patients of all ages.

Methods

Primary sources comparing insulin pens with vial and sy-ringe published from January 1980 to February 2008 weregathered from MEDLINE, EMBASE, CINAHL, CochraneDatabases, Cochrane Central Register of Controlled Trials,Cochrane Database of Systematic Reviews, and Database ofAbstracts of Reviews of Effects. In MEDLINE, EMBASE, andCINAHL, ‘‘insulin,’’ ‘‘pen,’’ ‘‘syringe,’’ and PROs (i.e., ‘‘satis-faction,’’ ‘‘acceptance,’’ ‘‘quality of life’’ (QoL), ‘‘preference,’’‘‘convenience,’’ and ‘‘pain’’) were utilized as the main keywords for the searches. Subject headings (e.g., MeSH) for‘‘insulin’’ and ‘‘diabetes’’ were combined with key words (andvariants) for ‘‘pen,’’ ‘‘vial,’’ or ‘‘syringe’’ and subject headingsand=or key words for the aforementioned PROs. Similarkeyword searches were conducted in the Cochrane databasesand the Database of Abstracts of Reviews of Effects to identifyrelevant systematic reviews. To maximize the search andmitigate potential publication bias, the following additionalsources were explored: doctoral theses, non–peer-reviewedjournals, references listed in reviews and=or primary sources,and meeting abstracts dated within the past 2 years found onthe websites of the American Diabetes Association and theEuropean Association for the Study of Diabetes.

Articles meeting the following selection criteria were in-cluded: (1) the study incorporated a comparative study designof insulin pen use versus vial and syringe use; (2) the studyincluded approaches to control for confounding and othertypes of potential bias; (3) the full text of the article included afull description of the study design, methods used to measureand assess PROs, and results; (4) the publication was writtenin English (translated non-English studies were included); (5)study subjects were children, adolescents, and=or adults withtype 1 diabetes (T1D) and=or T2D who, during the course ofthe study, used insulin pen devices and=or vial and syringe;and (6) the study evaluated patient preference and=or otheraforementioned PROs as either a primary or secondary ob-jective. In order to avoid bias in the selection of articles, twoindependent reviewers (C.M. and L.S.) determined study el-igibility. Any discrepancies between two independent re-viewers were resolved via adjudication and a third reviewer(M.S.) when necessary. Lastly, a data summary table (Table 1)was created to summarize the main study attributes (e.g.,study design, country, PROs, results) from each publication.Data within the summary table were reviewed for accuracyby two independent reviewers (L.S. and M.S.).

Results

Literature search

The database search yielded 124 publications, which in-cluded six review articles. Application of selection criteriaresulted in a total of 50 primary source articles by bothreviewers. Discrepancies between the two independent re-viewers were primarily associated with study design. Afterresolution of these discrepancies, 41 articles met the selectioncriteria and were included in this review. As shown in Table 1,these studies used a wide range of comparative study de-signs with varied follow-up periods ranging from 2 weeks to 5

years. Approximately 75% of the articles were published be-tween 1990 and 2008. A majority (78%) of the research studieswas conducted outside the United States. Most (>75%) of thestudies evaluated male and female patients with diabeteswith mean ages around 45 years. Some of the studies evalu-ated children with diabetes who were as young as 8 years oldand elderly patients as old as 79 years old.17,24,25,40

The objective(s) of some studies included a comparison of‘‘safety’’ and=or ‘‘efficacy’’ profiles between insulin penand vial and syringe use.14,16–19,21–27,30–41,43,44,46–49,51–54 Tobe consistent with our objective, the current review solelyfocused on PRO data. A majority (>90%) of these studiesmeasured PROs as a primary objective (see Table 1 for de-tails). Studies included in the current review did not provideexplicit conceptual and=or operational definitions of PROs,but, overall, PROs were measured using self-reported ques-tionnaires. The studies either measured the PRO directly orindirectly through specified PRO indicators. For example,depending on the study, ‘‘preference’’ was measured eitherdirectly by asking patients which delivery device they pre-ferred or indirectly via preference indicators such as ‘‘will-ingness to continue’’ or ‘‘recommend insulin pen use.’’ Insulinpen devices used by studies in the current review included theHumulin=Humalog� pen (Eli Lilly and Co., Indianapolis, IN),HumaPen� Ergo (Eli Lilly and Co.), NovoPen, NovoLet�

(Novo Nordisk A=S), BD� pens (Becton Dickinson, FranklinLakes, NJ), InnoLet� (Novo Nordisk A=S), Insuject� (NovoNordisk A=S), FlexPen� (Novo Nordisk A=S), and Optipen�

(sanofi-aventis, Paris, France).

Preference

Twenty-nine articles assessed preference as a primary PROmeasure.14,15,17–20,23–28,32–35,37–40,43–51 In 28 of these studies,the majority (>66%) of patients preferred insulin pen devicesover vial and syringe, or they chose and=or were willing tocontinue treatment with insulin pen devices instead of vialand syringe.14,15,17–20,23–28,32,34,35,37–40,43–51 For example, inone head-to-head study by Jorgensen et al.34 (1988), 48 out of50 patients with T1D reported a greater preference for theinsulin pen over vial and syringe. In a study by Bohannon andOhannesian20 (2000), 74% of 315 diabetes patients preferredthe pen to vial and syringe. Similar results were found inprospective studies in which patients reported greater pref-erence with their use of insulin pens when compared to theirprevious experience with using vial and syringe.20,38,50,51 Onestudy found similar preference profiles between insulin penand vial and syringe use.33

Acceptability

Twelve studies assessed acceptability,18,19,23,26,27,32,33,38,40,41,46,47

and in 10 of them (*80%), the majority (>75%) of patientsreported greater acceptance of the insulin pen devices com-pared to vial and syringe.19,23,26,27,32,38,40,41,46,47 For example,in a prospective study that included 100 patients with T1D orT2D, a significantly higher acceptance rate was found whenpatients switched from using vial and syringe to insulin pens(P< 0.01).41 Two studies did not report greater acceptabilitywith pen devices than vial and syringe.18,33 Hung and Wang33

(1992) measured insulin delivery, privacy, and dosage accu-racy as indicators of acceptability in a study that yieldedmixed results with regard to acceptability: in this study, 78%

530 MOLIFE ET AL.

Page 3: Assessment of Patient-Reported Outcomes of Insulin Pen Devices Versus Conventional Vial and Syringe

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Page 6: Assessment of Patient-Reported Outcomes of Insulin Pen Devices Versus Conventional Vial and Syringe

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Page 7: Assessment of Patient-Reported Outcomes of Insulin Pen Devices Versus Conventional Vial and Syringe

of the patients rated the insulin pen device as quicker than vialand syringe with regard to insulin delivery. Whereas 50% ofpatients reported more privacy when using the pen devicethan vial and syringe, the remaining 50% reported no differ-ence.33

Pain

Pain was measured as a PRO in nine stud-ies.17,19,24,25,29,30,33,35,36 All but one study reported the majority(>50%) patients experiencing less pain while using a pendevice than vial and syringe: in the study by Hung andWang33 (1992), the majority of patients (i.e., approximately67%) reported no difference in pain between the insulin pendevice and vial and syringe. In a study by Graff and McCla-nahan29 (1998), 507 participants with T1D or T2D were eval-uated, and 90% of them reported ‘‘little or no pain’’ with theinsulin pen device, whereas 62% reported ‘‘moderate tosevere’’ pain with vial and syringe.

QoL

Three36,49,53 of the eight studies16,18,21,22,36,49,52,53 that eval-uated QoL as a PRO found a greater improvement in QoLamong diabetes patients who used insulin pen devices com-pared to those who used vial and syringe. In contrast, studiesby Barnett et al.18 (1996), Chantelau et al.22 (1997), and An-derson and Wikby16 (1997) found no statistically significantdifferences with regards to QoL after using an insulin pendevice compared to vial and syringe. Studies by Buysschaertet al.21 (1988) and Tallroth et al.52 (1989) yielded mixed results.Tallroth et al.52 (1989) found no differences regarding moodand well-being, but showed that treatment using the insulinpen device resulted in increased experiences of freedom andflexibility in meal times.

Satisfaction

Five14,39,41,49,51 of the seven14,18,37,39,41,49,51 studies thatevaluated patient satisfaction with insulin pen devices com-pared to vial and syringe found that the majority (>76%) ofpatients reported higher treatment satisfaction from usinginsulin pen devices. For example, in a randomized, multi-center, two-period, crossover study by Stockl et al.49 (2007)with a sample of 260 T1D or T2D patients, patients had sig-nificantly greater treatment satisfaction (P< 0.0001) from us-ing the insulin pen device than the conventional vial andsyringe. Conversely, studies by Barnett et al.18 (1996) andKorytkowski et al.37 (2003), with samples of 93 and 121, re-spectively, found no statistically significant differences(P< 0.05) in treatment satisfaction between insulin pen deviceand vial and syringe use.

Convenience, handling, dosing, and ease of use

Ten studies evaluated convenience15,17,29,33,36,37,42,43,49,54

and two others evaluated handling and dosing associatedwith the delivery device.45,46 Eight of the 10 studies reportedthat the majority (56–100%) patients found insulin pendevices to be more convenient than vial and sy-ringe.15,17,29,33,36,43,49,54 In a study by Graff and McClanahan29

(1998), ease of use, facilitation of compliance, and quickness ofuse were used as indicators for convenience; in this study, themajority (86%) of the patients found insulin pen devices to be

easier to use than vial and syringe, 77% reported that pendevices facilitated compliance with their regimen, and 86%considered the pen devices quicker to use than vial and sy-ringe. A study by Korytkowski et al.37 (2003) found no sta-tistically significant difference in convenience between pendevices and vial and syringe. Schwartz et al.45 (2006) andShelmet et al.46 (2004) each conducted studies to evaluate PROassociated with handling and dosing. In a randomized, two-period, crossover study, incorporating a sample of 60 patientswith T2D, Schwartz et al.45 found that 92% of patients con-sidered the insulin pen device to be easier to use, 92% con-sidered handling to be easier, 88% found the insulin pendevice to be more reliable in drawing and dispensing insulin,and there was a significant reduction in overall administrationtime (P< 0.05) compared to vial and syringe.

All nine studies that evaluated ‘‘ease of use’’ found that themajority (�61%) of patients considered the insulin pen de-vices easier to use than vial and syringe.17,20,24,25,28,35,44,46,50

For example, Shelmet et al.46 (2004) reported that 84% of the79 patients with T2D found the insulin pen devices easier touse than the conventional vial and syringe.

Other PROs

Other studies evaluated the following as their primaryPRO: self-reported resource utilization (e.g., number ofphysician visits, hospitalization),45 effects on lifestyle=flexibility,15,29 self-concept,31 anxiety,31 dose-setting confi-dence,40 and overall evaluation.29 Regarding self-reportedresource utilization, studies by Schwartz et al.45 (2006) andShelmet et al.46 (2004) yielded results with patients reportingless nursing assistance with insulin pen devices than vial andsyringe. In a study by Houtzagers et al.32 (1989), patientanxiety, self-concept, and flexibility were found to be im-proved more with insulin pen than vial and syringe. Asso-ciated findings were consistently in favor of the insulin pendevice compared to vial and syringe.31

Discussion

Findings from this review are consistent with previousfindings regarding PROs associated with insulin pen deviceand vial and syringe use.8–13 However, our findings are rel-evant to a wider range of insulin pen devices than previousreviews because we did not limit our search to a particularinsulin pen brand or type. As the current review demon-strates, a strong body of evidence supports that insulinadministration via insulin pen devices is easier, more conve-nient, quicker, and less painful than vial and syringe, and it isassociated with greater patient preference and acceptability.Additionally, patients with diabetes are more satisfied withusing insulin pen devices and consider insulin pen devicesless conspicuous and more socially acceptable. These resultsare understandable considering insulin pen devices possess avariety of features, including dial-a-dose mechanism, half-unit dosing, memory of dose, time, and date of previousdoses, audible clicks, clear dial showing the selected dose, andportability.8,9,55

A variety of barriers to optimal diabetes managementhave been shown to be associated with insulin injectiontherapy. Insulin injection is perceived to be painful, and painhas been shown to be a significant barrier in adhering to

PATIENT-REPORTED OUTCOMES OF PEN VERSUS VIAL 535

Page 8: Assessment of Patient-Reported Outcomes of Insulin Pen Devices Versus Conventional Vial and Syringe

insulin regimens.9,17,19,24,25,29,30,33,35,36,56 Thus, the evidence inthe current review, demonstrating that insulin pen devicesgenerally facilitate less painful injections than vial and sy-ringe, is especially important. The current review also sup-ports that some patients with diabetes consider insulin pendevices to be more socially acceptable than vial and syringe,29

which may mitigate another barrier for adults and adolescentswho may feel more conspicuous carrying and using a vial andsyringe in public places. It has been reported that 60–80% ofpatients who use vial and syringe for insulin administrationincorrectly administer insulin because of timing and dosingerrors.57,58 Population subgroups at potential risk of dosingerrors include the elderly (>60 years), who represent ap-proximately 50% of all patients with diabetes in the UnitedStates,59 patients who are visually and physically impaired,children, adolescents, and their caregivers who may need tomeasure small doses.

Continuing refinement of insulin delivery devices (e.g.,pens, pumps) aim to improve glycemic control by facilitatingadherence to complex and sometimes intensive insulin ther-apy regimens.20 In a study by Vijan et al.60 (2005) that exam-ined patients’ views of the burden of diabetes therapy, itwas found that patients viewed insulin injection and self-monitoring of blood glucose as very burdensome. Patients’views of burden were the strongest consistent independentpredictor of self-rated levels of adherence to therapy, as wellas willingness to accept insulin therapy. Insights from theHealth Belief Model61,62 indicate that patients with diabeteswill more likely engage in optimal diabetes management be-haviors, such as adherence to prescribed insulin regimens, ifthe perceived threat of diabetes and benefits of adherence arehigh enough when balanced against barriers of engaging inthis behavior. In light of this, minimizing aforementionedbarriers to adherence (e.g., pain) via insulin delivery deviceattributes favored by patients, as evidenced by associatedPROs, may potentially increase patients’ self-efficacy and thelikelihood of adhering to prescribed insulin regimens.

Although this review employed approaches to mitigatebias (e.g., publication and study selection bias), some limita-tions are noteworthy. A majority (72%) of the examinedstudies was conducted before 2000, and some of the studiesexamined older pen devices that have been discontinued orwere never marketed. However, because findings were rep-licated in more recent studies, the potential for misclassifica-tion bias is minimal. Second, examined studies were notblinded; however, the sample was as unbiased as could beachieved in studies of this nature. Thirdly, because several ofthe examined studies had short follow-up periods (range,3–12 weeks), there may not have been sufficient time or op-portunity to examine any significant changes associated withPROs. In addition, some studies examined small sample sizes(i.e., <30 participants); therefore, interpretation of thesestudies’ findings may be limited. Last, studies varied widelyin the type and validation status of PRO questionnaires used,limiting our ability to make consistent comparisons acrossstudies.

Conclusions

Insulin pen devices are a preferred and more acceptableinsulin delivery system compared to conventional vial andsyringe. Additionally, insulin pen devices offer greater con-

venience, flexibility, treatment satisfaction, ease of use, per-ceived dosing accuracy, and self-efficacy and less pain, socialstigma, and insulin administration time, compared to vial andsyringe. These findings support how insulin pen device usecan potentially improve adherence to insulin therapy regi-mens. Diabetes care providers, patients, and payers can allcontribute to reducing barriers associated with conventionalinsulin therapy by incorporating favorable components (e.g.,well-accepted insulin delivery device) into diabetes manage-ment programs, practice, and=or protocols.

Acknowledgments

We thank Philip Walker for his assistance in literaturesearch. This review was financially supported by Eli Lilly andCompany.

Author Disclosure Statement

C.M., L.J.L., and S.M.L. are employees of Eli Lilly andCompany. L.S. and M.S. declare no competing financial in-terests.

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Address correspondence to:Cliff Molife, M.P.H.

Eli Lilly and CompanyDrop Code 5539

Indianapolis, IN 46285

E-mail: [email protected]

538 MOLIFE ET AL.