`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.
`
` 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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`

`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
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`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
`
`REFERENCE S
` 1. American Diabetes Association. Pharmacologic approaches to gly-
`cemic treatment. Diabetes Care. 2020;43:S98- S110.
` 2. Bydureon
`(exenatide)
`[package
`insert]. Wilmington, DE:
`AstraZeneca Pharmaceuticals LP; 2020.
` 3. Trulicity (dulaglutide) [package insert]. Indianapolis, IN: Eli Lilly and
`Company; 2020.
` 4. Ozempic (semaglutide) [package insert]. Plainsboro, NJ: Novo
`Nordisk; 2020.
` 5. Victoza (liraglutide) [package insert]. Plainsboro, NJ; 2020.
`
`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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`6 of 6  |    
`
` 6. Adlyxin (lixisenatide) [package insert]. Bridgewater, NJ: Sanofi-
`Aventis U.S. LLC; 2019.
` 7. Byetta (exenatide) [package insert].Wilmington, DE: AstraZeneca
`Pharmaceuticals LP; 2020.
` 8. Rybelsus (semaglutide) [package insert] Plainsboro, NJ: Novo
`Nordisk; 2019.
` 9. Coleman CI, Limone B, Sobieraj DM, et al. Dosing frequency and
`medication adherence in chronic disease. J Manage Care Pharm.
`2012;18:527- 539.
` 10. Weeda ER, Coleman CI, Mchorney CA, Crivera C, Schein JR,
`Sobieraj DM. Impact of once- or twice- daily dosing frequency on
`adherence to chronic cardiovascular disease medications: a meta-
`regression analysis. Int J Cardiol. 2016;216:104- 109.
` 11. Boye K, Curtis S, Lage M, Garcia- Perez L. Associations between
`adherence and outcomes among older, type 2 diabetes patients:
`evidence from a Medicare Supplemental database. Patient Prefer
`Adherence. 2016;10:1573- 1581.
` 12. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication non-
`adherence on hospitalization and mortality among patients with
`diabetes mellitus. Arch Intern Med. 2006;166:1836- 1841.
` 13. Covidence systematic review software, Veritas Health Innovation,
`Melbourne, Australia. www.covid ence.org
` 14. Pharmacy Quality Alliance. PQA Measure Overview. https://www.
`pqaal liance.org/asset s/Measu res/PQA%20Mea sure%20Ove rview
`%20082 018.pdf. Accessed September 20, 2019.
` 15. Dreyer NA, Bryant A, Velentgas P. The GRACE checklist: a validated
`assessment tool for high quality observational studies of comparative
`effectiveness. J Manag Care Spec Pharm. 2016;22:1107- 1113.
` 16. Page MJ, McKenzie J, Bossuyt P, et al. The PRISMA 2020 statement:
`an updated guideline for reporting systematic reviews. https://doi.
`org/10.31222/ osf.io/v7gm2
` 17. Yu M, Xie J, Fernandez Lando L, Kabul S, Swindle RW. Liraglutide
`versus exenatide once weekly: persistence, adherence, and early
`discontinuation. Clin Ther. 2016;38:149- 160.
` 18. Nguyen H, Dufour R, Caldwell- Tarr A. Glucagon- like pep-
`tide- 1 receptor agonist (GLP- 1RA) therapy adherence for pa-
`tients with type 2 diabetes in a medicare population. Adv Ther.
`2017;34:658- 673.
` 19. Alatorre C, Fernández Landó L, Yu M, et al. Treatment patterns in
`patients with type 2 diabetes mellitus treated with glucagon- like
`peptide- 1 receptor agonists: Higher adherence and persistence
`with dulaglutide compared with once weekly exenatide and liraglu-
`tide. Diabetes Obes Metab. 2017;19:953- 961.
` 20. Cai J, Wang Y, Baser O, Xie L, Chow W. Comparative persistence
`and adherence with newer anti- hyperglycemic agents to treat
`patients with type 2 diabetes in the United States. J Med Econ.
`2016;19:1175- 1186.
` 21. Buysman EK, Sikirica MV, Thayer SW, Bogart M, DuCharme MC,
`Joshi AV. Real- world comparison of treatment patterns and effec-
`tiveness of albiglutide and liraglutide. J Comp Eff Res. 2018;7:89- 100.
` 22. Mody R, Huang Q, Yu M, et al. Adherence, persistence, glycaemic
`control and costs among patients with type 2 diabetes initiating
`dulaglutide compared with liraglutide or exenatide once weekly
`at 12- month follow- up in a real- world setting in the United States.
`Diabetes Obes Metab. 2019;21:920- 929.
` 23. Qiao Q, Ouwens MJ, Grandy S, Johnsson K, Kostev K. Adherence
`to GLP- 1 receptor agonist therapy administered by once- daily or
`once weekly injection in patients with type 2 diabetes in Germany.
`Diabetes Metab Syndr Obes. 2016;9:201- 205.
` 24. Thieu VT, Robinson S, Kennedy- Martin T, Boye KS, Garcia- Perez LE.
`Patient preferences for glucagon- like peptide 1 receptor- agonist
`treatment attributes. Patient Prefer Adherence. 2019;13:561- 576.
`
` 25. Gelhorn HL, Bacci ED, Poon JL, Boye KS, Suzuki S, Babineaux SM.
`Evaluating preferences for profiles of glucagon- like peptide- 1 re-
`ceptor agonists among injection- naive type 2 diabetes patients in
`Japan. Patient Prefer Adherence. 2016;10:1337- 1348.
` 26. Gelhorn HL, Poon JL, Davies EW, Paczkowski R, Curtis SE, Boye
`KS. Evaluating preferences for profiles of GLP- 1 receptor agonists
`among injection- naïve type 2 diabetes patients in the UK. Patient
`Prefer Adherence. 2015;9:1611- 1622.
` 27. Hauber AB, Nguyen H, Posner J, Kalsekar I, Ruggles J. A discrete-
`choice experiment to quantify patient preferences for frequency of
`glucagon- like peptide- 1 receptor agonist injections in the treatment
`of type 2 diabetes. Curr Med Res Opin. 2016;32:251- 262.
` 28. Kim YY, Lee JS, Kang HJ, Park SM. Effect of medication adherence
`on long- term all- cause- mortality and hospitalization for cardiovas-
`cular disease in 65,067 newly diagnosed type 2 diabetes patients.
`Sci Rep. 2018;8:12190.
` 29. Egede LE, Gebregziabher M, Echols C, Lynch CP. Longitudinal
`effects of medication nonadherence on glycemic control. Ann
`Pharmacother. 2014;48:562- 570.
` 30. Bibeau WS, Fu H, Taylor AD, Kwan AY. Impact of out- of- pocket phar-
`macy costs on branded medication adherence among patients with
`type 2 diabetes. J Manage Care Spec Pharm. 2016;22:1338- 1347.
` 31. Zeng F, An JJ, Scully R, Barrington C, Patel BV, Nichol MB. The
`impact of value- based benefit design on adherence to diabetes
`medications: a propensity score- weighted difference in difference
`evaluation. Value Health. 2010;13:846- 852.
` 32. Karter AJ, Parker MM, Solomon MD, et al. Effect of out- of- pocket
`cost on medication initiation, adherence, and persistence among
`patients with type 2 diabetes: the diabetes study of Northern
`California (DISTANCE). Health Serv Res. 2018;53:1227- 1247.
` 33. DeJong C, Masuda C, Chen R, Kazi DS, Dudley RA, Tseng CW. Out-
`of- pocket costs for novel guideline- directed diabetes therapies
`under medicare part D. JAMA Internal Med. 2020;180:1696.
` 34. Stewart KD, Johnston JA, Matza LS, et al. Preference for phar-
`maceutical formulation and treatment process attributes. Patient
`Prefer Adherence. 2016;10:1385- 1399.
` 35. Giorgino F, Penfornis A, Pechtner V, Gentilella R, Corcos A.
`Adherence to antihyperglycemic medications and glucagon- like
`peptide 1- receptor agonists in type 2 diabetes: clinical conse-
`quences and strategies for improvement. Patient Prefer Adherence.
`2018;12:707- 719.
` 36. Johnston SS, Nguyen H, Felber E, et al. Retrospective study of ad-
`herence to glucagon- like peptide- 1 receptor agonist therapy in pa-
`tients with type 2 diabetes mellitus in the United States. Adv Ther.
`2014;31:1119- 1133.
`
`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/
`ijcp.14060
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`WEEDA Et Al.
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