`Received: 18 November 2020 | Accepted: 23 January 2021
`DOI: 10.1111/ijcp.14060
`
`M E T A - A N A LY S I S
`METABOLISM&ENDOCRINOLOGY
`
`Medicationadherencetoinjectableglucagon-likepeptide-1
`(GLP-1)receptoragonistsdosedonceweeklyvsoncedailyin
`patientswithtype2diabetes:Ameta-analysis
`
`ErinR.Weeda |AlyssaK.Muraoka |MatthewD.Brock |JessicaM.Cannon
`
`Medical University of South Carolina College
`of Pharmacy, Charleston, SC, USA
`
`Correspondence
`Erin R. Weeda, Medical University of South
`Carolina College of Pharmacy, Charleston,
`SC, USA.
`Email: weeda@musc.edu
`
`Abstract
`Background:Suboptimal medication adherence has been associated with increased
`resource utilisation and mortality among patients with type 2 diabetes (T2D).
`Glucagon- like peptide- 1 receptor agonists (GLP- 1RAs) are becoming increasingly im-
`portant in the treatment of T2D. However, medications in this class differ consider-
`ably in their dosing frequency, which may impact adherence. We sought to perform
`a meta- analysis to compare adherence to injectable GLP- 1RAs dosed once weekly vs
`once daily in patients with T2D.
`Methods: Medline and Scopus were searched from 1/2005 to 7/2020 using key-
`words and MeSH terms pertaining to adherence and GLP- 1RAs. Studies of adults
`with T2D were included if they compared adherence (as measured by proportion
`of days covered [PDC]) to injectable GLP- 1RAs dosed once weekly vs once daily.
`A meta- analysis of non- overlapping studies was performed to evaluate the primary
`outcome of non- adherence, defined as the proportion of patients with a PDC < 80.
`Results:A total of 7 studies evaluating 75 159 patients (range: 2886- 30 097) with
`T2D were included. The follow- up periods of included studies ranged from 6 to
`12 months. Injectable GLP- 1RAs dosed once weekly were either dulaglutide, albi-
`glutide or exenatide extended release; while liraglutide was the injectable once daily
`agent evaluated in all included studies. Upon meta- analysis, once weekly GLP- 1RA
`dosing was associated with an 11% lower risk of non- adherence compared to once
`daily dosing (risk ratio = 0.89; 95% confidence interval = 0.83- 0.95; I2 = 89%).
`Conclusion:Once weekly dosing of injectable GLP- 1RAs was associated with better
`adherence vs once daily dosing among patients with T2D. These findings coupled
`with the known detrimental consequences of non- adherence suggest that dosing
`frequency is an important factor to consider when selecting a GLP- 1RA.
`
`1 | INTRODUCTION
`
`Glucagon- like peptide- 1 receptor agonists (GLP- 1RAs) are becom-
`ing increasingly important in the treatment of type 2 diabetes.1
`According to American Diabetes Association guidelines, GLP- 1RAs
`with proven cardiovascular benefits should be considered in indi-
`viduals with diabetes and atherosclerotic cardiovascular disease,
`
`regardless of baseline A1C. GLP- 1RAs are also a treatment option
`for individuals who are not well controlled on first- line therapy (ie,
`metformin and lifestyle interventions), especially among patients
`who could benefit from weight loss or a regimen that minimises the
`risk of hypoglycaemic events.
`GLP- 1RAs differ in their dosing frequency with some dosed once
` weekly (eg, exenatide extended- release [ER], dulaglutide, injectable
` | 1 of 6
`
`Int J Clin Pract. 2021;75:e14060.
`https://doi.org/10.1111/ijcp.14060
`
`wileyonlinelibrary.com/journal/ijcp
`
`© 2021 John Wiley & Sons Ltd
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`2 of 6 |
`
`semaglutide, albiglutide) and others requiring administration each day
`(eg, liraglutide and lixisenatide which are dosed daily and exenatide
`which is dosed twice daily).2- 8 Studies assessing adherence in chronic
`diseases, like diabetes, demonstrate that less frequent dosing results in
`higher medication adherence.9,10 This coupled with the fact that con-
`sequences of non- adherence with diabetes medications include poor
`glycaemic control, higher healthcare costs, increased risk of hospital-
`isation and even mortality, makes dosing frequency an important factor
`to consider when selecting therapy.11,12 While studies have evaluated
`adherence to GLP- 1RAs, the relationship between dosing frequency
`and adherence to GLP- 1RAs has yet to be systematically summarised.
`We sought to perform a meta- analysis comparing adherence to inject-
`able GLP- 1RAs dosed once weekly vs once daily in patients with T2D.
`
`2 | METHODS
`
`2.1 | Searchstrategy
`
`To identify articles for inclusion in this meta- analysis, a systematic litera-
`ture search was conducted from January 2005 (the year a GLP- 1RA was
`first approved by the United States [US] Food and Drug Administration
`[FDA]) to July 2020 in Medline and Scopus using keywords and MeSH
`terms related to GLP- 1RAs and adherence (Table S1).7 To supplement
`the search, we also performed backwards citation tracking.
`
`2.2 | Studyselection
`
`All studies were screened independently for inclusion in Covidence
`systematic review software by two investigators with any disagree-
`ments resolved by a third investigator.13 In order to be included, arti-
`cles had to be real- world studies of adults with type 2 diabetes that
`compared adherence to once weekly vs once daily dosing of inject-
`able GLP- 1RAs. Clinically meaningful differences in adherence have
`been observed between agents dosed once- vs twice- daily9,10; thus,
`we made a priori decision to evaluate once daily dosing and exclude
`evaluations of GLP- 1RAs dosed twice- daily, as it would likely be in-
`appropriate to combine these two frequencies into a single cohort
`of daily dosing. Studies measuring adherence by any metric other
`than proportion of covered days (PDC) were excluded, as PDC is
`considered a preferred method to measure medication adherence.14
`Only studies published in the full- text form were included. In order
`to avoid correlation in results, overlapping patient populations, as
`identified by timing of the sample and data source, were excluded.
`If overlapping populations were identified, the study with the most
`generalisability (eg, largest sample size) was included.
`
`2.3 | Dataabstraction
`
`We used a standardised data abstraction tool to collect data from
`all studies including timing of sample, data source, follow- up time,
`
`What’sknown
`• Glucagon- like peptide- 1 receptor agonists (GLP- 1RAs)
`are becoming increasingly important in the treatment of
`type 2 diabetes.
`• GLP- 1RAs differ in their dosing frequency, which may
`impact adherence.
`
`What’snew
`• Once weekly dosing of injectable GLP- 1RAs was asso-
`ciated with better adherence when compared to once
`daily dosing of injectable GLP- 1RAs.
`• These findings coupled with the known detrimental
`consequences of non- adherence suggest that dosing
`frequency is an important factor to consider when se-
`lecting a GLP- 1RA.
`
`Reviewcriteria
`• Studies of adults with type 2 diabetes were included if
`they compared adherence (as measured by proportion
`of days covered [PDC]) to injectable GLP- 1RAs dosed
`once weekly vs once daily.
`
`Messagefortheclinician
`• Our findings of increased adherence with once weekly
`dosing are consistent with numerous studies demon-
`strating that patients with type 2 diabetes tend to pre-
`fer once weekly over once daily dosing, likely due to the
`increased convenience of once weekly dosing.
`
`demographics of patients (eg, age, sex), proportion of patients
`on each injectable GLP- 1RA and proportion of patients with a
`PDC < 80. One investigator entered all data, with a second investi-
`gator verifying data entries. Next, we used the GRACE tool to assess
`the internal validity of each included study and evaluated nine items
`across the data and method domains.15 Two investigators indepen-
`dently reviewed each study. If a study met a criterion for that item, a
`(Y) was designated, otherwise a (N) was recorded.
`
`2.4 | Datasynthesis
`
`The primary outcome of this study was non- adherence, defined as
`the proportion of patients with a PDC < 80.14 We used the Hartung-
`Knapp random- effects model to estimate risk ratios with 95%
`confidence intervals (CIs). The I2 statistic assessed the per cent of
`variability attributed to heterogeneity, with a >50% considered sub-
`stantial heterogeneity. In addition to analysing all included studies,
`we performed two subgroup analyses. The first subgroup analysis
`excluded studies that did not take covariates into consideration, as
`
`WEEDA Et Al.
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` 17421241, 2021, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijcp.14060 by Sayem Osman , Wiley Online Library on [14/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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`F I G U R E1 PRISMA: preferred
`reporting items for systematic reviews
`and meta- analyses flow diagram. PDC,
`Proportion of days covered; QD, once
`daily; QW, once weekly. *This article was
`excluded due to overlap with Yu et al and
`is cited as reference 36
`
` | 3 of 6
`
`TA B L E1 Characteristics of studies evaluating adherence to injectable GLP- 1 receptor agonists
`
`Firstauthor,
`year(N)
`Mody 201922
`(4854)
`Alatorre 201719
`(4074)
`
`Buysman
`201721 (4426)
`Nguyen 201718
`(4210)
`
`Cai 201620
`(2886)
`
`Qiao 201623
`(30 097)
`
`Yu 201617
`(24 612)
`
`Datasource,country
`
`Timingofsample
`
`Follow-up
`time,months
`
`November 2014- May
`2016
`November 2014- April
`2015
`
`July 2014- December
`2015
`January
`2010- February 2014
`
`February 2014- July
`2014
`
`January
`2011- December 2013
`
`February 2012- March
`2013
`
`12
`
`6
`
`12
`
`6
`
`12
`
`6
`
`6
`
`HealthCore Integrated
`Research Database, US
`Truven Health Market
`Scan Commercial
`Claims and Encounters
`and Medicare
`Supplemental
`Databases, US
`Optum Research
`Database, US
`Humana Administrative
`Claims Database -
`Medicare members, US
`Truven Health Market
`Scan Commercial
`Claims and Encounters
`and Medicare
`Supplemental
`Databases, US
`IMS Health Longitudinal
`Prescriptions Database,
`Germany
`Truven Health Market
`Scan Commercial
`Claims and Encounters
`and Medicare
`Supplemental
`Databases, US
`
`GLP-1RA,n(%)
`Dulaglutidea , 2427 (50)
`Liraglutide, 2427 (50)
`Dulaglutidea , 2037 (50)
`Liraglutide, 2037 (50)
`
`Male
`(%)
`
`48%
`
`Age
`(mean±SD)
`54.3 ± 9.6
`
`47%
`
`54.2 ± 10.1
`
`Albiglutide, 2213 (50)
`Liraglutide, 2213 (50)
`Exenatide ER, 537 (12.8)
`Liraglutide, 3673 (87.2)
`
`53%
`
`47%
`
`52.4 ± 9.0
`
`70.8 ± 4.1
`
`Exenatide ER, 883 (30.6)
`Liraglutide, 2003 (69.4)
`
`50%
`
`52.4 ± 9.8
`
`Exenatide ER, 5449 (18.1)
`Liraglutide, 24 648 (81.9)
`
`50%
`
`59.5 ± 11.5
`
`Exenatide ER, 12 306 (50)
`Liraglutide, 12 306 (50)
`
`49%
`
`55.3 ± 9.9
`
`Abbreviations: ER, extended release; GLP- 1RA, glucagon- like peptide- 1 receptor agonists; US, United States.
`aThis study included dulaglutide, liraglutide and exenatide ER. However, the study only matched those receiving exenatide ER to those receiving
`dulaglutide, with a second matched analysis of those receiving dulaglutide versus liraglutide. Therefore, the only comparison available for use in our
`meta- analysis was dulaglutide versus liraglutide.
`
`WEEDA Et Al.
`
` 17421241, 2021, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijcp.14060 by Sayem Osman , Wiley Online Library on [14/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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`Novo Nordisk Exhibit 2014
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`
`
`y
`
`y
`
`y
`
`y
`
`n
`
`n
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
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`y
`
`y
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`y
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`y
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`y
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`y
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`y
`
`y
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`y
`
`y
`
`y
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`y
`
`y
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`y
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`y
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`y
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`y
`
`y
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`y
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`y
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`y
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`y
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`y
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`y
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`y
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`y
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`y
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`y
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`y
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`y
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`y
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`y
`
`Yu17
`Qiao23
`Cai20
`Nguyen18
`Buysman21
`Alatorre19
`Mody22
`
`intoconsideration
`covariatestaken
`Important
`
`comparators
`concurrent
`groupswere
`Comparison
`
`treatment
`newinitiatorsof
`restrictedto
`Studypopulation
`
`recorded
`confounders
`maybeknown
`Covariatesthat
`
`comparisongroups
`treatmentand
`measuredbetween
`Primaryoutcome(s)
`
`similarpopulation
`validatedina
`outcome(s)
`Primary
`
`objectively
`measured
`outcome(s)
`Primaryclinical
`
`recorded
`adequately
`outcome(s)
`Primary
`
`recorded
`adequately
`exposure
`Treatment
`
`Methods
`
`Data
`
`TABLE2 GRACE Quality Assessment Tool
`
`4 of 6 |
`
`assessed by the GRACE tool. The second subgroup analysis included
`only studies evaluating exenatide ER. The ‘meta’ package in R ver-
`sion 3.5.2 (www.r- proje ct.org) was used for all analyses. This work
`was completed in accordance with the Preferred Reporting Items for
`Systematic reviews and Meta- Analyses (PRISMA) Statement.16
`
`3 | RESULTS
`
`Of the 515 records screened for inclusion, 485 and 23 were ex-
`cluded after title/abstract and full- text screening (Figure 1). The re-
`maining 7 studies were included in the meta- analysis and evaluated
`75 159 patients (range: 2886- 30 097) with type 2 diabetes receiving
`injectable GLP- 1RAs (Table 1).17- 23 A total of 49 307 (65.6%) patients
`received agents with once daily dosing, while 25 852 (34.4%) pa-
`tients received once weekly dosing. GLP- 1RAs dosed once weekly
`were either dulaglutide, albiglutide or exenatide ER; while liraglutide
`was the once daily agent evaluated in all included studies. Median
`follow- up time across the studies ranged from 6 to 12 months. The
`mean age of patients included in the studies ranged from 52.4 to
`70.8 years and approximately half were male.
`All seven studies were given a “Y” for eight of the evaluated
`items and five studies were given a “Y” for the ninth item because
`they utilised matching to account for covariates (Table 2). Two stud-
`ies did not meet the criteria for important covariates taken into
`consideration.
`The proportion of patients with non- adherence (ie, a PDC < 80)
`ranged from 51% to 72% across included studies. Upon meta-
`analysis, once weekly dosing was associated with an 11% lower risk
`of non- adherence compared to once daily dosing (Figure 2; P < .05).
`The I2 statistic for this analysis was 89% (P < .01). Consistent results
`were observed when studies that did not meet the GRACE tool crite-
`rion for taking covariates into consideration were excluded from the
`analysis (risk ratio [RR] = 0.86; 95% confidence interval [CI] 0.80-
`0.93; I2 = 88%, P <.01). When we assessed only studies evaluating
`exenatide ER, which was the most common once weekly GLP- 1RA
`in included studies, the direction of the effect was similar but no
`statistical difference between dosing frequencies was observed
`(RR = 0.93; 95% CI = 0.84- 1.02). Heterogeneity in this analysis was
`similar to the aforementioned analyses (I2 = 82%; P < .01).
`
`4 | DISCUSSION
`
`In this meta- analysis assessing adherence to injectable GLP- 1RAs,
`once weekly dosing was associated with higher adherence when
`compared to daily administration. We hypothesise that our findings
`are a result of the convenience of once weekly dosing, as numerous
`studies suggest that less frequent GLP- RA dosing frequency is the
`most important medication attribute to patients.24- 27 For instance,
`in a discrete- choice experiment survey of 643 individuals with type
`2 diabetes in the US, changing from daily to weekly dosing had the
`greatest influence on treatment choice and was more important to
`
`WEEDA Et Al.
`
` 17421241, 2021, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijcp.14060 by Sayem Osman , Wiley Online Library on [14/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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`
`F I G U R E2 Forest Plot of included
`studies comparing adherence to once
` weekly versus once daily dosing. CI,
`confidence interval; PDC, Proportion of
`days covered
`
` | 5 of 6
`
`patients than device type, needle size, injection- site reactions and
`the need to refrigerate a device.27
`The finding of decreased adherence with once daily vs once
` weekly dosing is important as medication non- adherence is associ-
`ated with poorer disease control, increased hospitalisations, higher
`healthcare costs and even mortality among individuals with type 2
`diabetes.11,12,28,29 In a study of 11 000 US Veterans with type 2 di-
`abetes, each 1% increase in adherence as measured by the medica-
`tion possession ratio, resulted in a 48% decrease in the odds of poor
`glycaemic control (P < .05). Moreover, among 11 532 US patients
`with diabetes, non- adherence was associated with increased odds
`of all- cause hospitalisation (odds ratio [OR] 1.58; 95% confidence
`interval [CI], 1.38- 1.81) and all- cause mortality (OR 1.81; 95% CI,
`1.46- 2.23).12 Increased adherence can also result in decreased treat-
`ment costs.11 In a study of medical costs including US patients 65
`and older with type 2 diabetes, a 1% increase in adherence among
`1000 patients was associated with savings of $65 464 over a 3- year
`period.11 These relationships demonstrate that adherence is an im-
`portant factor to consider when selecting an anti- hyperglycaemic
`agent. Nonetheless, it should be noted that adherence is one of
`many factors that influence metabolic control and thus impact short
`and long- term consequences of suboptimal control of diabetes.
`In addition to dosing frequency, there are several other import-
`ant factors that may impact adherence to GLP- 1RAs. For example,
`high out- of- pocket medication costs are known to negatively impact
`adherence.30- 32 Out- of- pocket costs are especially relevant to the
`use of GLP- 1RAs, as 2019 Medicare Part D list prices of novel di-
`abetes drugs, including GLP- 1RAs, were 40 to 360 times the cost
`of other diabetes medications such as sulphonylureas and thiazo-
`lidinediones.33 This difference in price then translated to a one to
`eightfold increase in patient out- of- pocket costs, where patients
`paying $250 to $355 annually for traditional medications are pro-
`jected to pay $1231 to $1981 for novel regimens.33 The use of oral vs
`injectable GLP- 1RAs may also impact adherence.34 As the first oral
`GLP- 1RA (oral semaglutide)8 was approved by the US FDA in 2019,
`there were no real- world studies evaluating adherence to this agent
`to include in our meta- analysis and thus, future studies are needed.
`Several limitations existed in our meta- analysis, including the
`observed heterogeneity. One explanation for this heterogeneity is
`the inclusion of different GLP- 1RAs dosed once weekly. These med-
`ications use different delivery devices and require different injec-
`tion administration techniques, which could impact adherence.2- 4,35
`
`However, the degree of heterogeneity was similar when we only in-
`cluded studies evaluating the most common GLP- 1RA, exenatide ER,
`in the analysis. Another explanation for the observed heterogeneity
`could be that some studies accounted for covariates, while others
`did not. Nonetheless, when we removed studies not accounting for
`confounders from the analysis, this did not have a meaningful im-
`pact on the amount of heterogeneity observed. Heterogeneity could
`have also been present because included studies differed in their
`follow- up time, with some studies measuring adherence over a 12-
`month period and others over a 6- month period. Similar to all meta-
`analyses, the validity of our analysis was dependent on the quality
`of included studies. If bias exists in included studies, meta- analysing
`the studies does not fix this.
`In conclusion, once weekly dosing of injectable GLP- 1RAs was
`associated with better adherence when compared to once daily dos-
`ing among patients with type 2 diabetes. Our findings are consistent
`with numerous studies demonstrating that patients with type 2 dia-
`betes tend to prefer once weekly over once daily dosing, likely due to
`the increased convenience of once weekly dosing. Dosing frequency
`is an important factor to consider when selecting a GLP- 1RA, es-
`pecially considering the well- established association between non-
`adherence and higher healthcare costs and increased morbidity and
`mortality among patients with type 2 diabetes.
`
`ACKNOWLEDGEMENTS
`None
`
`DISCLOSURE
`The authors have no conflicts of interest related to this manuscript.
`
`ORCID
`Erin R. Weeda
`
` https://orcid.org/0000-0001-7876-5802
`
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` 17421241, 2021, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijcp.14060 by Sayem Osman , Wiley Online Library on [14/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`
`Novo Nordisk Exhibit 2014
`Mylan Pharms. Inc. v. Novo Nordisk A/S
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`SUPPORTINGINFORMATION
`Additional Supporting Information may be found online in the
`Supporting Information section.
`
`Howtocitethisarticle: Weeda ER, Muraoka AK, Brock MD,
`Cannon JM. Medication adherence to injectable glucagon- like
`peptide- 1 (GLP- 1) receptor agonists dosed once weekly vs
`once daily in patients with type 2 diabetes: A meta- analysis. Int
`J Clin Pract. 2021;75:e14060. https://doi.org/10.1111/
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`WEEDA Et Al.
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` 17421241, 2021, 9, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijcp.14060 by Sayem Osman , Wiley Online Library on [14/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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