Exploring variables associated with medication non-adherence in patients with type 2 diabetes mellitus.

OBJECTIVE: This study aims to assess medication adherence and explore its predictors in outpatients with type 2 diabetes.
METHOD: This cross-sectional study collected socio-demographics, disease-related information, and different biomedical variables for type 2 diabetes patients attending a Jordanian Diabetes center. The four-item medication adherence scale (4-IMAS) and the beliefs about medications questionnaire (BMQ) which includes necessity and concerns were used. Stepwise backward quartile regression models were conducted to evaluate variables associated with the Necessity and Concerns scores. Stepwise ordinal regression was conducted to evaluate variables associated with adherence.
RESULTS: 287 diabetic patients participated in the study. Almost half of the participants (46.5%) reported moderate adherence and 12.2% reported low adherence. Significant predictors of the adherence were necessity score (OR = 14.86, p <0.01), concern score (OR = 0.36, p <0.05), and frequency of medication administration (OR = 0.88, p- <0.01). Education was a significant predictor of Necessity and Concerns scores (β = 0.48, -0.2, respectively).
CONCLUSION: Simplifying the medication regimen, emphasizing medication necessity and overcoming medication concerns should be targeted in future diabetes intervention programs to improve medication adherence and hence glycemic control among diabetic patients.

Introduction

Diabetes mellitus is the most common endocrine chronic disease, affecting 5–10% of the general population [1]. It is predicted that the number of diabetic patients will reach 592 million by 2035 [2]. Because of the high morbidity and mortality rates from the disease, diabetes represents a significant economic burden in many countries [3,4]. Evidence-based studies indicate that glycemic control is one of the most important predictors of mortality and morbidity in patients with diabetes [5]. Epidemiological analysis of the United Kingdom Prospective Diabetes Study (UKPDS) revealed that a reduction in HbA1c% corresponds to a reduction in incidence of myocardial infarction, stroke, and microvascular complications [6]. However, despite the variety of available diabetes treatments, only 50% of diabetic patients can manage to achieve adequate glycemic control (HbA1c% <7%) [7]. In Jordan, only 34% of the diabetic patients who are visiting the National Center for Diabetes, Endocrinology and Genetics (NCDEG) had achieved the HbA1c% target [8].

One of the key contributors to glycemic control is medication adherence; which is defined by the World Health Organization as “the degree to which the person’s behavior corresponds with the agreed recommendations from a health care provider” [9]. The causal relationship between glycemic control and medication adherence had been established by several studies [10-12]. Moreover, medication non-adherence raises the risk of diabetes complications which will also increase the burden of the disease and its management [10]. Several factors have been identified as associated with medication non-adherence in patients with different chronic diseases including type 2 diabetes. These factors include patients’ sex, their beliefs about medications, disease duration, and education level [13,14]. Therefore, evaluating patients’ level of adherence and exploring the factors associated with poor medication adherence should provide insight on implementing diabetes management intervention programs to improve patients’ adherence and hence glycemic control among patients with type 2 diabetes. Hence, this study aims to evaluate medication adherence and its associated factors among outpatients with type 2 diabetes.

Methods

Study site and participants

A cross-sectional study was conducted. Participants were recruited from the National Center for Diabetes, Endocrinology and Genetics (NCDEG) outpatient clinic in Amman, Jordan. NCDEG is one of the largest diabetes clinics in Jordan providing services to more than 324,000 patients per year [15].the Services the clinic provides include diabetes education, dietary management, and diabetic foot care [15]. The enrolled participants were patients of 18 years of age or older who had been diagnosed with type 2 diabetes for one year or more, and were taking at least one anti-diabetic medication.

Sample size calculation

The equation used to compute the minimum required sample size to ‎conduct ordinal ‎regression is: required sample size = 50+8P, where p is the number of predictors. The study aimed to assess the association ‎of different medication usage, age, gender education and income levels, necessity and concerns scores, and diabetes duration with adherence level. In total the study aimed to evaluate the association between 22 variables and adherence level therefore, the minimum required sample size is 226 subjects. However, the univariate analysis indicated that only three variables out of the evaluated 22 were significantly associated with adherence level and therefore, only these three variables were included in the final ordinal regression model. ‎.‎

Study procedure

‎Out of 360 patients who met the inclusion criteria and were approached and invited to participate by the physicians and the assigned researcher at the NCDEG diabetes clinics between January 2020 and December 2020, a total of 287 patients agreed to participate with a response rate of 79.7%. The participants signed an informed consent form that included all study details. The researcher explained the study objectives to the patients and assured them that participation was voluntary. No incentives were provided. Participants were interviewed at private rooms in NCDEG and each interview lasted for about 15 minutes. Study ethical approvals were obtained from Al-Zaytoonah ethical committee (ethical approval number 22/23/2019-2020) and NCDEG research ethics committee (ethical approval number 1/2020).

Study instruments

Socio-demographics

The following socio-demographic data were collected: age, sex, household monthly average income, and education level. The average household monthly income in Jordan is 1000 JOD [16]; therefore, participants were categorized into low and high-income groups based on this figure. Participants were also categorized into a low educational group that includes those with diploma degree or less and high education group that includes those with bachelors or postgraduate degrees. Disease factors were reported such as duration of diabetes and HbA1c%, medication-related variables including types of medications, medications frequencies and cost, and the number prescribed medications were collected for each participant using patients’ medical files in NCDEG.

Beliefs about medicines questionnaire (BMQ)-specific

The validated Arabic version of the BMQ-specific [17] (S3 and S4 Appendixes) was used to assess participants’ positive beliefs represented as perception of medicines’ necessity (Necessity statements) and participants’ negative beliefs represented as concerns about the medicines (Concerns statements) [18]. Each part consisted of five statements of 5-point Likert scale. The responses for the statements were 1: “Strongly disagree”, 2:“Disagree”, 3:“Not certain”, 4:“Agree” and 5:“Strongly disagree”. Means for both parts were computed; these means were considered Necessity score and Concerns score.

The 4-item medication adherence scale

The validated Arabic version of the 4-IMAS [19,20] (S1 and S2 Appendixes) was used with “Yes” or “No” responses. The adherence score was the sum of the responses for the 4 items as “Yes” response was given 1 point and “No” was given zero points. The participants were divided into three groups: Low adherence for the participants with a score of three or more, moderate adherence group for those with one or two points, and high adherence group for those with a score of zero.

Medication cost

The total cost of diabetic medication was calculated based on the sum of the monthly price of each medication. The price list was obtained from the NCDEG.

Pilot study

Although the Arabic version of the questionnaires were previously validated. Nevertheless, the questionnaires (socio-demographic sheet, 4-IMAS, and BMQ-specific) were presented to 30 participants that met the inclusion criteria. The participants confirmed that all the questions were clear and comprehensible. The data of the subjects that participated in the pilot study were excluded from the final data.

Statistical analysis

SPSS Version 26 was used to analyze the data [21]. Categorical variables were presented as frequencies (%), while continuous variables were expresses as means (SD). Univariable analysis was conducted and variables with p-values less than <0.05 were included in the regression models. Internal consistency of 4-IMAS, Necessity and Concerns statements was evaluated using Cronbach’s alpha. The normality of Concerns and Necessity scores were assessed, and normality assumption were not met, therefore stepwise quantile regression models were conducted to evaluate variables associated with the Necessity and Concerns scores. A stepwise ordinal regression was conducted to evaluate variables associated with adherence level. The model included adherence level (low, moderate, or high adherence) as the dependent variable, while the independent variables include Necessity score, Concerns score, and medications frequency (variables that were significantly associated with adherence level in the Univariable analysis). Because of the high significant correlation between total medication cost, number of medication and medication frequency, only medication frequency was included in the model. Moreover, to maintain adequate cell count assumption; several medications with expected cell count ≤ 5 were removed. P-values of less than 0.05 were considered to be significant.

Results

Two hundred and eighty-seven diabetic patients participated in the study with a response rate of 79.7%. As shown in Table 1, the mean age of the participants was 56(±14). More than half of the participants (54.7%) were females. The participants were divided into a low-income group (42.9%) and high-income group (57.1%). The majority of the participants (77.4%) had an education level of diploma or less.

Table 1

Socio-demographics.

		Frequency (%) or Mean (SD)
Age		56(14)
Gender	Female	157(54.7)
	Male	130(45.3)
Household monthly average income	Low income	123(42.9)
	High income	164(57.1)
Education level	Low education	222(77.4)
	High education	65(22.6)

Disease and medication characteristics are presented in Table 2. The duration of disease ranged between 1 year and 21 years with a mean of 3.04(±3.52). The mean of the number of medications that participants were on is 6.66(±3.36) and the highest number of the prescribed medications was twenty. Many of the participants were taking more than one type of antidiabetic medication and Metformin was the most taken medication (86.4%), followed by sulfonylurea (31.0%) and Dipeptidyl peptidase ((DDP-4) Inhibitors (28.9%). The most common prescribed non-antidiabetic medication was statin (39.4%).

Table 2

Disease and medications characteristics of the participants.

		Frequency (%) or Mean (±SD)
Diabetes duration		6.04(±3.52)
Number of medications		6.66(±3.36)
Diabetic of medications	Metformin	248(86.4)
	DDP4- Inhibitors	83(28.9)
	Sulfonylurea	89(31.0)
	SGLT2 Inhibitors	13(4.5)
	Insulin	105(36.6)
Other Medications	Statins	113(39.4)
	Beta Blockers	47(16.4)
	Nitrates	8(2.8)
	Gabapentin	11(3.9)
	Diuretics	27(9.5)
	ARBs	55(19.3)
	CCB	26(9.1)
	ACEI	14(4.9)
	PPI	57(19.9)

DDP4: Dipeptidyl peptidase-4, SGLT2: Sodium-Glucose Cotransporter-2, ARBs: Angiotensin Receptor Blocker, CCB: Calcium Channel Blocker, ACEI: Angiotensin Convertor Enzyme Inhibitor, PPI: Proton Pump Inhibitor.

The BMQ-specific statements’ means are shown in Table 3. Internal consistencies for Necessity and Concerns statements were confirmed by Cronbach’s alpha (0.93 and 0.81 respectively). The Quantile regression indicated that lower education level (β = 0.2, p = 0.003) and statin administration (β = 0.2, p<0.001) were associated with increased concerns score, while increased education level (β = 0.48, p = 0.001) was associated with increased necessity score.

Table 3

Beliefs about medicines questionnaire.

	Mean(±SD)
Specific Necessity	3.55(±0.79)
My health, at present, depends on my medicines	3.52(±0.91)
My life would be impossible without my medicines	3.46(±0.92)
Without my medicines I would become very ill	3.61(±0.85)
My health in the future will depend on my medicines	3.56(±0.90)
My medicines protect me from becoming worse	3.60(±0.87)
Specific Concerns	3.08(±0.49)
Having to take medicines worries me	3.16(±0.61)
I sometimes worry about the long-term effects of my medicines	3.08(±0.75)
My medicines are a mystery to me	3.02(±0.64)
My medicines disrupt my life	3.00(±0.49)
I sometimes worry about becoming too dependent on my medicines	3.13(±0.72)

Participants’ adherence levels and their responses to the 4-IMAS are shown in Table 4. The computed Cronbach’s alpha indicated acceptable internal consistency (0.74). Most of the participants reported moderate adherence (46.7%), followed by high adherence (41.1%) and lastly low adherence (12.2%). The most common form of non-adherence was forgetfulness (57.1%) while stopping the medication when feeling worse was the least form of non-adherence (13.9%).

Table 4

The 4-item medication adherence scale.

Adherence statements		Mean (±SD) or frequency (%)
Ever forget to take medicines (Yes)		164(57.1)
Ever careless about taking medicines (Yes)		56(19.5)
Stop taking medicines when feeling better (Yes)		44(15.3)
Stop taking medicines if you feel worse (Yes)		40(13.9)
Total score		1.06(±1.20)
Adherence level		Frequency (%)
Low		35(12.2)
Moderate		134(46.7)
High		118(41.1)

The mean cost of diabetic medications was 28.33 JOD (±29.13) and the maximum monthly cost was 160.64 JOD/month. SGLT-2 inhibitors drug class had the highest cost and Sulfonylurea drug class had the lowest.

As shown in Table 5, results of ordinal regression revealed that increasing medications frequency (OR = 0.88, p-value<0.05) and increased medication concerns score (OR = 0.36, p-value <0.01) were associated with decreased medication adherence, while increased necessity score was significantly associated with increased medication adherence (OR = 14.86, p-value <0.01).

Table 5

Ordinal regression of adherence level.

		Low adherence vs. High adherence
	B	P-value	Odds Ration	Confidence Interval of 95%
				Lower	Upper
Medications frequency	-0.13	0.032	0.88	0.79	0.99
Necessity score	2.70	<0.01	14.86	0.20	0.67
Concerns score	-1.02	<0.01	0.36	8.69	25.42

Discussion

Diabetes medications including oral and injectable hypoglycemic agents are highly effective in disease management if taken properly [22]. Studies have shown that diabetic patients’ adherence to oral hypoglycemic agents varies between 36% and 93% [23] and the overall adherence levels are greatly below average [24]. Among this study’s participants, 12.2% were low adherent, this percentage is lower than the ones reported among the diabetic patients’ in studies conducted in Nigeria [25], USA [26], Palestine [27], and Saudi Arabia [28]. However, there is still a room for improvement as for instance, a study conducted in Ghana reported a percentage of 8% of low adherence level in participants [29]. These variations in reported adherence levels between different studies may be attributed to differences in methodologies (i.e., questionnaires used) and sample characteristics. The threshold for acceptable medication non-adherence among diabetic patients is yet to determine, but a French crowdsourcing study reported that according to medical doctors’ opinions, one daily missed dose per month of insulin therapy is considered unacceptable [30]. Therefore, in addition to poor adherence, moderate adherence among diabetic patients also should be improved. A study that evaluated medication adherence in Jordanian patients with different chronic diseases who were taking five medications or more found that 46.1.% of the participants reported low adherence [31]. Higher rate of non—adherence (72.5%) was reported among outpatients with type 2 diabetes in Jordan [32]. The current study enrolled patients from a specialized diabetes center (NCDEG) and used additional instruments to determine the factors associated with adherence, including BMQ when compared with the earlier study by Jarab et al. [32].

Several modifiable and non-modifiable predictors of adherence level were investigated in the literature. A number of non-modifiable predictors had been found to be significantly but inconsistently associated with adherence level including sex and education level [26,33,34]. However, none of these variables was significantly associated with medication adherence in the present study. Nevertheless, education level was significantly associated with the participants’ beliefs about medication which in turn was significantly associated with adherence level. Focus on modifiable predictors including factors related to behavioral aspects [35], costs [36], and therapy regimens complexity [37] has recently increased. Consistent with earlier research findings [25,27,38,39], patients’ beliefs about diabetes medications was significantly associated with medication adherence in the present study. The same result was also observed in studies conducted on a sample of patients with different multiple chronic diseases [40], and on those with specific diseases such as cardiovascular diseases [41] dyslipidemia [17], and asthma [42]. In the current study, better patients’ medication beliefs, represented as increased perception of the necessity of their medication, was associated with improved medication adherence. The role of healthcare providers in this aspect can be substantial where they can emphasize the important role of medications in improving disease management and health outcomes, which in turn motivates the patients to take the medications as recommended.

Increased patients’ concerns about their medications was found to negatively impact medication adherence in the present study, as well as an unwillingness to initiate new therapies [43,44]. Therefore, exploring patient’s concerns about their medications and resolving any potential barriers to take the medication as prescribed should be considered in future patient-centered interventions aimed at improving medication adherence and hence glycemic control and health outcomes among patients with type 2 diabetes. Moreover, team-based care that includes pharmacists had been found as an effective strategy to give patients opportunities to raise their concerns, which in turn, improves their adherence [45,46].

Due to the strong association between medication adherence and patients’ beliefs about medications observed in the current study, it is necessary to investigate the variables which are associated with medication beliefs. Similar to a previous study [47], lower education level was associated with lower perception of medication necessity and increased concerns about the medications. Therefore, exploring the benefits of diabetes medications in controlling blood glucose and the serious complications which could be developed due to medication non-adherence should be explored for patients with a low level of education, particularly in during the delivery of disease management intervention programs. Similar to the current study findings, previous studies found that the administration of statins, particularly high-intensity statins, was associated with decreased medication adherence due to increased concerns related to potential adverse medication effects [48], this could lead to poor disease control and hence poor quality of life among statin recipients [49].

Consistent with the findings from a systemic review of 20 studies which all reported a negative impact of increased medication frequency on medication adherence [50], we also found that increased medication frequency was associated with decreased medication adherence in the present study. Simplifying dosage regimen by prescribing fixed-dose combinations [51] and medications with long half-lives should be considered in future diabetes management intervention programs.

Limitations

Because some of the study results were based on self-reported data which were not independently confirmed, the results are subject to recall bias. Moreover, as the questionnaires were completed by the interviewer based on the participants’ ‎responses, the study results are subject to social desirability and interviewer bias, However, to reduce the effect of the interviewer bias each question was read exactly as it appears to the participants without paraphrasing or interpretation. Selection bias could be another limitation of the study as participants who were interested in the study objectives would be more encouraged to participate in the study. Moreover, the results of the current study are based on the data from one center only, however, the NCDEG is the only specialized center for diabetes in Jordan and receives patients from all over the kingdom.

Conclusion

The current study findings show that there is area for medication adherence improvement among patients with type 2 diabetes. In addition to consider simple dosage regimen, enhancing diabetes medication necessity and exploring medication concerns should be prioritized in future diabetes management intervention programs, particularly for patients with a lower level of educational.

Medication adherence questionnaire (Arabic).

(DOCX)

Click here for additional data file.

Medication adherence questionnaire (English).

(DOCX)

Click here for additional data file.

Beliefs about medications (BMQ)-general questionnaire (Arabic).

(DOCX)

Click here for additional data file.

Beliefs about medications (BMQ)-general questionnaire (English).

(DOCX)

Click here for additional data file.

1 Jul 2021

PONE-D-21-17503

Exploring variables associated with medication non-adherence in patients with type 2 diabetes mellitus

PLOS ONE

Dear Dr. Al-Qerem,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I have received the reports from our advisors on your manuscript which you submitted to PLOS ONE.

Based on the comments received, I feel that your manuscript could be reconsidered for publication should you be prepared to incorporate major revisions.

When preparing your revised manuscript, you are asked to carefully consider the reviewer comments below and submit a list of responses to the comments.

Editor Comments: The paper should be checked by a professional speaker of English before complete acceptance.

Please submit your revised manuscript by Aug 15 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Sajid Hamid Akash

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

3. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information. If the original language is written in non-Latin characters, for example Amharic, Chinese, or Korean, please use a file format that ensures these characters are visible.

4. Please state whether you validated the questionnaire prior to testing on study participants. Please provide details regarding the validation group within the methods section.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Comments to editor and authors

Thank you for submitting this interesting manuscript that that evaluated the factors associated with non-adherence among diabetic Jordanians. The study is well written however, I have few comments that should be addressed.

-Major point:

Add sample size calculations.

-Minor point:

Please identify the study type in the methods (abstract and manuscript).

Please clarify that necessity and concerns are the BMQ parts in the method-abstract.

Please add OR values to the results section in the abstract

Line 120: The sentence is not clear.

The abbreviation of Hemoglobin A1c% is HbA1c%, please modify the manuscript accordingly.

In table 2 footnotes, please add the CCBs abbreviation clarification.

Line 26: add a coma after information.

Line 33: add “a” before significant predictor.

Line 199: Remove “a” before studies.

Line 204: remove “on”

Reviewer #2: Several minor errors in grammar/English were in the paper. There were also some long paragraphs (eg introduction is a single paragraph). Please proofread.

Refer to 'subjects' as 'participants' throughout manuscript.

For ease, please also add the response rate as a percentage.

In the Study site and subjects section, information on data collection was included. This should be placed in a separate Procedure section. Interviews are referred to (line 82), but the instruments used were questionnaires. Does this mean that the questions were read to participants? If so, this needs to be acknowledged in the limitations in the Discussion section.

Add references to the English and Arabic versions of the BMQ in the section starting on line 96.

Explain why the percentages for medications in Table 2 add up to more than 100% (presumably this means that participants were taking more than one medication for their diabetes, but this needs to be clarified).

The Discussion section is well-written and evaluates the literature well. A minor issue is the use of reference 27 which is a survey of doctors. Isn’t there any evidence-based research on the consequences of non-adherence? Opinion isn’t the same as evidence.

Reviewer #3: Dear Editor,

Thank you for giving me the chance to review this manuscript. The manuscript has some issues, which I report below. Thank you.

• Line 32: “Results: “… About half of the participants (46.5%) were moderate adherents”

I believe the study focuses on medication non-adherence, as evident in the title, so the non-adherence rate should be reported in the results in the abstract unless the author wishes to change the title for consistency.

• Line 33: “Higher necessity mean was significant predictor of high adherence”:

This should be modified to something like: necessity score was a significant predictor of adherence----similar modification is needed for concern score and frequency.

• Line 47 :”…it's expected that the number of diabetic patients will reach 592 47 million by 2035.”

The year the author referred to here is the wrong one; please correct.

• Line 64”….. These factors include sex, beliefs about 64 medications, disease duration, and education level..”

Reword this to refer to “ the patient”. e.g, patient’s gender…..

• Line 74: “NCDEG is one of the largest 74 diabetes clinics in Jordan and its’ visitors exceed 324,000 per year”

Rewording is needed

• Line 84: …”Study ethical approvals were 84 obtained from Al-Zaytoonah ethical committee and NCDEG committee.”

More details about the number of ethical approval are needed here

• Line 105

Please also cite the study that validated the Arabic version of the 4-IMAS

• Line 147 “…highest mean in Necessity statements was for “Without my medicines I would become very ill” (3.61±0.85), and the lowest mean was for “My life would be impossible without my medicines” (3.46±0.92).”

I don’t think such details add value, especially that the highest and lowest means are very close to each other same for the concerns statement

• Line 130

The line shows an abrupt start of the results section, referring to Table one. I suggest a smoother introduction of the result section, talking about the number of participants, response rate,….

• Line 177 : The authors wrote, “Among this study’s participants, 12.2% were low adherent, this percentage is lower than the ones reported among the diabetic patients’ in studies conducted in Nigeria[22], USA[23], Palestine[24], and Saudi Arabia[25]. However, there is still a room for improvement as other studies had reported better adherence levels[20,26].”

What room for improvement they meant? The sentence does not add up; please modify by comparing your non-adherence rates with other studies justifying the difference

• Line 183 “…Therefore, moderate adherence among diabetic patients also should be improved.”

Why moderate? Where did you conclude this? Did you mean both moderate and poor adherence levels? Then you better clarify this.

• Line 194: “…..However, none of these variables was significantly associated with 195 medication adherence in the present study.”

The study did not explore ethnicity or comorbidities as predictors of adherence, so the statement isn't valid

• Line 202: “…Better patients’ medication beliefs, represented as 202 increased perception of the medications’ necessity, was associated with improved medication 203 adherence.”

Were the authors here referring to their results? Please specify. This is seen in multiple places throughout the manuscript.

• Line 239: “The current study findings show a good margin for medication adherence improvement among patients with type 2 diabetes.”

I do not see 12% non adherence as a good margin; please rephrase the conclusion.

• Some English language issues and some terminology needs to be revised through the text such as “low educated” which should be replaced with: low levels of education”…..

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Eman Alefishat

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: Comments.docx

Click here for additional data file.

18 Jul 2021

Dear Editor,

We would like to thank the editor and reviewers for their efforts and time. We appreciate the reviewers’ comments, and we believe that their comments significantly improved the quality of the manuscript. We believe that we have addressed all the comments raised by the reviewers and the editor.

Regards

Editor Comments: The paper should be checked by a professional speaker of English before complete acceptance.

- Thank you for this, the manuscript has been revised by a native English speaking professional.

Reviewer #1: Comments to editor and authors

Thank you for submitting this interesting manuscript that that evaluated the factors associated with non-adherence among diabetic Jordanians. The study is well written however, I have few comments that should be addressed.

-Major point:

Add sample size calculations.

- Thank you for your comments. Sample size calculation has been added as suggested.

-Minor point:

Please identify the study type in the methods (abstract and manuscript).

- The study type has been added.

Please clarify that necessity and concerns are the BMQ parts in the method-abstract.

- Thank you for your comment. The abstract has been modified accordingly.

"The four-item medication adherence scale (4-IMAS) and the beliefs about medications ‎questionnaire (BMQ) which includes necessity and concerns were used."

Please add OR values to the results section in the abstract

- The ORs were added.

Line 120: The sentence is not clear.

- The sentence has been deleted.

The abbreviation of Hemoglobin A1c% is HbA1c%, please modify the manuscript accordingly.

- Thank you for this; the abbreviation was corrected throughout the manuscript.

In table 2 footnotes, please add the CCBs abbreviation clarification.

- The abbreviation was added.

Line 26: add a coma after information.

- The coma was added.

Line 33: add “a” before significant predictor.

- The “a” was added.

Line 199: Remove “a” before studies.

- The “a” was removed.

Line 204: remove “on”

- The “on” was removed.

Reviewer #2: Several minor errors in grammar/English were in the paper. There were also some long paragraphs (eg introduction is a single paragraph). Please proofread.

- Thank you for this, the manuscript has been revised by a native English speaking professional.

Refer to 'subjects' as 'participants' throughout manuscript.

- The manuscript was modified accordingly.

For ease, please also add the response rate as a percentage.

- The response rate percentage was added.

In the Study site and subjects section, information on data collection was included. This should be placed in a separate Procedure section. Interviews are referred to (line 82), but the instruments used were questionnaires. Does this mean that the questions were read to participants? If so, this needs to be acknowledged in the limitations in the

- A separate section of the procedure has been added and the limitation section modified.

“Furthermore, as the questionnaires were completed by the interviewer based on the participants’ ‎responses, the study results are subjected to social desirability and interviewer bias, However, in order to reduce the effect of the interviewer bias each question was read exactly as it appears to the participants without paraphrasing or interpretation.”‎

Discussion section.

Add references to the English and Arabic versions of the BMQ in the section starting on line 96.

- Thank you for this. The references have been added.

Explain why the percentages for medications in Table 2 add up to more than 100% (presumably this means that participants were taking more than one medication for their diabetes, but this needs to be clarified).

- Thank you for this. This is now explained in the results and the following was added:

“Many of the participants were taking more than one type of antidiabetic medication and Metformin was the most frequently taken medication (86.4%),… “

The Discussion section is well-written and evaluates the literature well. A minor issue is the use of reference 27 which is a survey of doctors. Isn’t there any evidence-based research on the consequences of non-adherence? Opinion isn’t the same as evidence.

- Thank you for this. We agree with the reviewer and the following was added to the sentence to clarify that it was only doctors’ opinions

“a French crowdsourcing study reported that according to the medical doctors’ opinions”

Reviewer #3: Dear Editor,

Thank you for giving me the chance to review this manuscript. The manuscript has some issues, which I report below. Thank you.

• Line 32: “Results: “… About half of the participants (46.5%) were moderate adherents”

I believe the study focuses on medication non-adherence, as evident in the title, so the non-adherence rate should be reported in the results in the abstract unless the author wishes to change the title for consistency.

- Thank you for this. The percentage of low adherents has been added to the abstract.

• Line 33: “Higher necessity mean was significant predictor of high adherence”:

This should be modified to something like: necessity score was a significant predictor of adherence----similar modification is needed for concern score and frequency.

- The abstract was modified accordingly.

“The significant predictors of the adherence level were necessity score (OR=14.86, p-value <0.01), ‎concern score (OR=0.36, p-value <0.05), and frequency of medication administration (OR=0.88, ‎p-value <0.01)."

Line 47 :”…it's expected that the number of diabetic patients will reach 592 47 million by 2035.”

The year the author referred to here is the wrong one; please correct.

- Thank you for pointing this out. The reference that contained the correct year was added and the previous reference was removed.

• Line 64”….. These factors include sex, beliefs about 64 medications, disease duration, and education level..”

Reword this to refer to “ the patient”. e.g, patient’s gender…..

- The sentence was reworded.

(These factors include patients’ sex, their beliefs about medications, disease duration, and ‎education level.)

• Line 74: “NCDEG is one of the largest 74 diabetes clinics in Jordan and its’ visitors exceed 324,000 per year”

Rewording is needed

- The sentence was reworded.

NCDEG is one of the largest diabetes clinics in Jordan providing services to more than 324,000 patients per year.)

• Line 84: …”Study ethical approvals were 84 obtained from Al-Zaytoonah ethical committee and NCDEG committee.”

More details about the number of ethical approval are needed here

- The ethical approval numbers has been added.

• Line 105

Please also cite the study that validated the Arabic version of the 4-IMAS

- Thank you for this; a reference has now been added

• Line 147 “…highest mean in Necessity statements was for “Without my medicines I would become very ill” (3.61±0.85), and the lowest mean was for “My life would be impossible without my medicines” (3.46±0.92).”

I don’t think such details add value, especially that the highest and lowest means are very close to each other same for the concerns statement

- This sentence has been removed.

• Line 130

The line shows an abrupt start of the results section, referring to Table one. I suggest a smoother introduction of the result section, talking about the number of participants, response rate,….

- The introduction to the Results section has been modified.

Two hundred and eighty seven diabetic patients participated in the study with a response rate of ‎‎79.7%. As shown in Table 1, the mean age of the participants was 56(±14)). ‎

• Line 177 : The authors wrote, “Among this study’s participants, 12.2% were low adherent, this percentage is lower than the ones reported among the diabetic patients’ in studies conducted in Nigeria[22], USA[23], Palestine[24], and Saudi Arabia[25]. However, there is still a room for improvement as other studies had reported better adherence levels[20,26].”

What room for improvement they meant? The sentence does not add up; please modify by comparing your non-adherence rates with other studies justifying the difference

- Thank you for this. Reference to a lower rate of non-adherence reported in another study has been added and justification for different results was included.

However, there is still a room for improvement as, for instance, a study conducted in Ghana ‎reported a percentage of 8% of low adherence level among its’ participants‎. These variation in reported adherence levels between different studies may be attributed to differences in methodologies (i.e., questionnaires used) and sample characteristics

• Line 183 “…Therefore, moderate adherence among diabetic patients also should be improved.”

Why moderate? Where did you conclude this? Did you mean both moderate and poor adherence levels? Then you better clarify this.

- The sentence was clarified.

Therefore, in addition to poor adherence, moderate adherence among diabetic patients also ‎should be improved.

• Line 194: “…..However, none of these variables was significantly associated with 195 medication adherence in the present study.”

The study did not explore ethnicity or comorbidities as predictors of adherence, so the statement isn't valid

- Reference to ethnicity and comorbidities has been removed.

• Line 202: “…Better patients’ medication beliefs, represented as 202 increased perception of the medications’ necessity, was associated with improved medication 203 adherence.”

Were the authors here referring to their results? Please specify. This is seen in multiple places throughout the manuscript.

- The sentence was modified.

In the current study, better patients’ medication beliefs, represented as increased.

• Line 239: “The current study findings show a good margin for medication adherence improvement among patients with type 2 diabetes.”

I do not see 12% non adherence as a good margin; please rephrase the conclusion.

- The conclusion has been rephrased.

The current study findings show that there is area for medication adherence improvement ‎among patients with type 2 diabetes.

• Some English language issues and some terminology needs to be revised through the text such as “low educated” which should be replaced with: low levels of education”…..

- The sentence has been modified.

which could be developed due to medication non-adherence should be explored for patients with ‎low level of education in particular during the delivery of disease management intervention ‎programs

- The whole manuscript has been revised by a native English speaker who is an academic.

Changes on references:

- Reference two (Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and ‎regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: ‎Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes ‎Res Clin Pract [Internet]. 2019 Nov 1 [cited 2021 Jan 7];157. Available from: ‎https://pubmed.ncbi.nlm.nih.gov/31518657/‎) was replaced with (Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global ‎estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin ‎Pract. 2014 Feb;103(2):137–49. ‎)

- References for BMQ (References 17 and 18) were added and the reference for the Arabic version of 4-IMAS was added (Reference 20).

Submitted filename: Responses to reviewers.docx

Click here for additional data file.

12 Aug 2021

Exploring variables associated with medication non-adherence in patients with type 2 diabetes mellitus

PONE-D-21-17503R1

Dear Dr. Al-Qerem,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Muhammad Sajid Hamid Akash

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

13 Aug 2021

PONE-D-21-17503R1

Exploring variables associated with medication non-adherence in patients with type 2 diabetes mellitus

Dear Dr. Al-Qerem:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Muhammad Sajid Hamid Akash

Academic Editor

PLOS ONE