Factors Associated With Non-Adherence To Antidiabetic Medication Among Patients at Mbarara Regional Referral Hospital, Mbarara, Uganda

Background Non–adherence is a major concern in treatment of diabetes mellitus and undermines the goals of treatment. The objective of this study was to determine the magnitude of non-adherence and its contributing factors among diabetes mellitus patients attending the Diabetes mellitus clinic at Mbarara Regional Referral Hospital. Objective To assess the factors contributing to non-adherence to antidiabetic medication among diabetes mellitus patients in the Diabetic clinic at Mbarara Regional Referral Hospital Methods A descriptive cross-sectional study was done at the Diabetes clinic, Mbarara Regional Referral Hospital, between July and October 2020. Study participants were systemically sampled and data regarding their medication non-adherence was collected using a structured questionnaire, based on the Hill-Bone medication adherence scale. Data entry was done using Microsoft Excel Version 2010 and analysis was carried out using STATA version 13.


Introduction
Diabetes mellitus (DM) is a major public health issue globally. Current estimates indicate that nearly 415 million people are affected and is set to escalate to 642 million by the year 2040, a further 193 million people with diabetes remain undiagnosed due to the often mild or asymptomatic nature of this condition especially in type 2 DM (T2DM) (1) Adherence to anti-diabetic medication is one of the major pillars of health service excellence and is de ned as the proportion of the prescribed doses of the drug actually taken by a patient over a speci ed period of time or the extent to which the patient is taking their medicines as prescribed by a health care professional (2).
Non-adherence to antidiabetic medication remains the most common reason for poor health outcomes among people with diabetes. The levels of non-adherence to antidiabetic recommendations are highly variable, but have signi cant effects on diabetes outcomes and the effectiveness of treatments (3,4).
Continuous evaluation of adherence is vital to identify factors and barriers contributing to non-adherence and its better management through timely identi cation of contributing factors and provision of individualized suitable recommendations that are essential for better healthcare management (5).
Poor persistence with and adherence to antidiabetic medication exposes the patient to disease complications with fatal consequences, including failure to achieve glycemic control goals (6), Contributes to the suboptimal glycemic control and continues to be one of the major barriers to effective diabetes mellitus management (7).
A study in India, established that 55.14% of the study participants were non-adherent and the Major contributing factors of non-adherence to antidiabetic treatment were ignorance for life style modi cation i.e. 83.78%. Among them, 59.48% didn't take the prescribed medicine in time, most of them 85.71% didn't follow diabetes diet and less than half (46.61%) didn't monitor blood glucose level regularly due to poor self-discipline. Gender, occupation and educational status were the signi cant contributors to nonadherence (8).
In Saudi Arabia, a therapeutic non-compliance prevalence of 67.9% (i.e. 69.34% in males and 65.45% in females) was largely associated with females, illiteracy, urban population, irregularity of follow-ups, nonadherence to antidiabetic medication, non-adherence to exercise regimen, insulin, and insulin with oral Metformin (9).
A study done by Gertrude Afriye and others at the University of Ghana among 259 patients within the ages of 26 years and 88 years established a proportion of non-adherence to antidiabetic medication of 34.7%. and associated factors that turned out to be statistically signi cant for non-adherence included; Age, educational level, presence of comorbidities, and nancial support (10). while in Ethiopia at Adama Hospital medical college, The prevalence of non-adherence was 58.6% (95% CI: 54.7, 62.4) and major depressive disorder, one or more diabetes mellitus complications, and average income greater than 1000 birr were found to be independent predictors of medication non-adherence respectively (11).
At a general hospital in Ethiopia, a non-adherence to antidiabetic medication prevalence of 31.2% amongst diabetes mellitus patients was established while side effects of medications, complexity of regimen, failure to remember, educational level and monthly income were major associated factors identi ed in the study (12).
Fewer studies on non-adherence to antidiabetic medication have been conducted in Uganda. However, a non-adherence prevalence to antidiabetic medication of 28.9% at Mulago hospital in Kampala district was mainly associated with female gender, illiteracy, low social economic status, poor handwriting on prescriptions, and delayed intervals to follow up on treatments (13).Hence, this study aimed at determining the prevalence and identifying factors associated with non-adherence to anti-diabetes medication among patients in the Diabetes mellitus clinic at Mbarara regional Referral hospital, south western Uganda.

Methods And Materials
Study setting and population The study was conducted in the Diabetes mellitus clinic at Mbarara Regional Referral Hospital (MRRH) located in Mbarara City, Mbarara district, south western region, Uganda from July to October 2020; it is a government owned referral and teaching hospital for Mbarara University Medical School with patient capacity of approximately of 350 beds. The general medical care in the hospital is free and the Diabetes mellitus clinic is one of the major ambulatory clinics operated once a week within the hospital. The study population was diabetes mellitus patients (both type 1 and type 2) who attended the Diabetes clinic at MRRH between July and October, 2020.

Study design
Descriptive cross-sectional study was done, Outcome variables were Non-adherence prevalence and Factors contributing to non-adherence to antidiabetic medication Sampling procedure and sample size Estimation The sample size was calculated using nite population formula and the prevalence of non-adherence to antidiabetic medication of 28.9% in Uganda by (13) was used for this calculation. Using formula (14); Where: Zα = Standard deviation at 95% con dence interval corresponding to 1.96 p = assumed population of diabetes mellitus patients who are non-adherent to treatment, results of a study at Mulago hospital (13) were used, so P = 28.9% 1-P = is the probability of diabetes mellitus patients who were adhering to their antidiabetic medication, Systematic random sampling technique was used to select study participants.
Sampling interval = 1074 / 257 = 4, interviewed every fourth patient on the clinic appointment list starting from a number randomly selected from 1 to 4 Data collection procedure Structured investigator-administered pre-tested questionnaire was used for each participant to collect information on socio-demographic and adherence characteristics. A check list was used to document diseases (Diabetes mellitus and other comorbidities) and drugs' (antidiabetic medication) information for each patient.
A detailed history was acquired (English), translated where necessary for patients who do not understand English.
Non-adherence to antidiabetic medication was assessed based on the Hill-Bone Medication Adherence scale (15).

Data Quality control
A registered nurse in the Diabetes clinic was recruited and well trained on data collection techniques. The data collection instruments were pretested on ve (5) patients in the Diabetes clinic to identify possible sources of errors that would arise during data collection. Those ve patients were not part of the sample population and the questionnaire was administered to them to measure the inter-respondent agreement. The agreement of more than 78% was a measure that the items of the questionnaire would provide a picture on factors associated with non -adherence to antidiabetic medication in the study population.
Inclusion and exclusion criteria were strictly adhered to. A common pretested questionnaire which was edited prior to its use was used for data collection. The questionnaire was also checked for completeness before data collection to ensure valid data was obtained. Identi cation of participants was done by means of numerical codes. Details of participants were kept under lock and key for privacy and con dentiality purpose throughout the course of the study. There was no disclosure of participants' identity to the public and all identities were removed before publication.

Data management and statistical analysis
Data on questionnaires was checked for completeness, coded and entered in Microsoft Excel version 2010, and then exported to stata version 13. Socio-demographic and clinical factors were summarized as means and standard deviation (for continuous variables). Percentages and frequencies were used for categorical variables. Descriptive statistics (means, frequencies and percentages) were used to determine prevalence of non-adherence and patient and disease information. The factors associated with nonadherence to antidiabetic medication were identi ed using logistic regression. Binary logistic Regression was carried out using stata. Prevalence Ratios were used to compare the prevalence of non-adherence across the independent variables. Factors with p-value ≤ 0.20 at bivariate logistic regression and with biological plausibility were considered for multivariate analysis. Those factors with p-value < 0.05 were considered signi cant.

Ethical considerations
This study was conducted in accordance with the Declaration of Helsinki (16). Approval to carry out the study was acquired from the Department of Pharmacy, Faculty of Medicine and nally from Mbarara University Research Ethics Committee (MUST-REC). After approval by the MUST-REC (Letter with reference number MUREC 1/7), permission was thought from the administration of Mbarara Regional Referral Hospital prior to data collection in the Diabetes mellitus clinic.

Precautions for prevention of Covid 19 transmission
Participants who were initially screened for body temperature and possible signs and symptoms of covid 19 were considered for data collection. These were further given more information on how covid 19 is transmitted and nally preventive measures of hand washing, wearing face mask and social distancing were always emphasized before any interaction with the study participants.

Results
The study had a response rate of 100% of 257 respondents.
Socio-Demographic Characteristics of Participants.

Prevalence of non-adherence
Over one third (98, 38.1%) of the study participants were non adherent to antidiabetic medication (Fig. 1).
Reasons for Non-adherence to Antidiabetic Medication More than one quarter (50, 25.5%) of the study participants reported that drug(s) being expensive was the cause for antidiabetic medication non-adherence and Less than one quarter (38, 19.4%) ascribed nonadherence to not understanding instruction(s) on how to take prescribed medicine(s) and less than one quarter (32, 16.3%) of the study participants attributed non-adherence to unavailability of the drug product to them (Table 4).    being expensive was the cause of antidiabetic medication non-adherence and less than one quarter (38, 19.4%) ascribed non-adherence to not understanding instruction(s) on how to take prescribed medicine(s). More than one third (98, 38.1%) of the participants were non-adherent to their antidiabetic medication. Multivariate logistic regression revealed that age above 60 years (AOR = 6.26, 95%CI = 1.009-39.241, P = 0.049) and duration of diabetes mellitus of above 5 years since diagnosis (AOR = 1.87, 95%CI = 1.034-3.391, P = 0.038) were independently associated with antidiabetic medication non adherence.
More than one-third (38.1%) of participants in our study were determined to be non-adherent to their antidiabetic medication. Reasons for non-adherence ranged from; drugs being expensive for patients to buy on daily basis (25.5%), lack of understanding of prescription instructions (19.4%), unavailability of free antidiabetic medicines in public hospitals (16.3%), forgetfulness (12.2%) and patients' preference for not following prescription instructions (12.2%).The ndings in our study, revealed a higher prevalence of non-adherence to antidiabetic medication compared to similar studies in UAE, Egypt, Ghana, Mulago Hospital in Uganda, and Tanzania; which reported between 16.0% and 31.5% prevalence of medication non-adherence among diabetes mellitus (4,5,13,17,18). Perhaps this may be due to differences in the study populations and the study settings of different studies. Findings of our study in which majority (214, 83.3%) of the participants had comorbidities are comparable to the results of the study by (19)where comorbidities were signi cantly linked to antidiabetic medication non-adherence. The explanation could be that, the number of drugs taken by each patient is dependent on comorbidities.
Therefore, a patient with a complex regimen is challenged to continue adhering to all prescribed medications. Multiple medications could contribute to non-adherence since such patients have divided commitment to managing several comorbidities. Also, since majority of our study population had low or no formal education (166,64.7%), this could explain the high levels of non-adherence to antidiabetic medications as further reported by previous studies in Ghana (20). The reason for this nding could be that as the antidiabetic regimen becomes complex, those with higher level of education are expected to easily understand such and thus effectively follow their treatment regimen. However, the ndings of our study are notably lower, with the prevalence of non-adherence to antidiabetic medication at 38.1% compared to 48-68.8% prevalence, as reported from multiple studies in Bosnia & Herzegovina, India, Saudi Arabia and Ethiopia(8, 9,21,22). This difference might be that in our study, patients regularly received free antidiabetic medications whenever available at the Diabetes clinic. Free supply of antidiabetic medicines is believed to reduce the level of non-adherence among patients (Kalyango et al., 2008). The other reason might be that in our study, patients were well organized in a patient association that provided psychological support and counseling to patients. The lower prevalence of non-adherence in our study settings could also be explained by the lower levels of forgetfulness (12.3%) and lack of nances (25.5%), as compared to similar studies in Sudan, Ghana, and Saudi Arabia, which reported 30.7-66.7%, and 23.8-25.6% frequencies of forgetfulness and lack of nances, respectively (17,23,24).
Since our study population majorly consisted of the female gender (168, 65.37%); ndings from our study revealed that the female gender was 57 % less likely to non-adhere to their antidiabetic medication (AOR = 0.57 95%CI = 0.312-1.044 p-value = 0.069). This is in agreement with ndings by (25), stating that the female gender were more adherent to their antidiabetic medications, possibly due to the reason that most females spent most of their time at home and are thus more likely to follow prescription instructions agreed upon with the prescribers due to convenient home environment.
Multivariate logistic regression revealed that, increasing age above 24 years had a positive association with likelihood of non-adherence to antidiabetic medication. Age groups between 24-60 years and above 60 years were 1.1 times (AOR = 1.19, 95% CI = 0.204-6.962, p-value = 0.845) and 6.2 times (AOR = 6.29 95% CI = 1.009-39.241 p-value = 0.049) more likely to be non-adherent to their antidiabetic medication, respectively. This nding in our study may be due to the fact that older adults are more likely to forget to take their medication and also older adults in our setting are less nancially capable to access medications from drug outlets, as prescribed by the healthcare provider. This will as well explain the contrasting ndings in a previous study in Ethiopia, where older adults were more likely to be adherent to their antidiabetic medication due to the possible difference in social-economic support to the elderly people (22). Duration of diabetes mellitus for more than 5years since diagnosis was also signi cantly associated with non-adherence to antidiabetic medication (AOR = 1.87, 95% CI = 1.034-3.391, P = 0.038). this is in agreement with the study from Saudi Arabia (3,24). It demonstrates that, the longer the duration of diabetes mellitus, the more the rate of non-adherence. This nding may be explained by the anxiety and fear that patients experience during early years following diagnosis and thus become committed to managing their disease but the commitment gradually wears out as they adapt to the burden of the disease and non-adherence emerges. Surprisingly, in the current study, being unemployed (AOR = 0.37, 95%CI = 0.139-0.977, p-value = 0.045) was protective and therefore less likely to lead to non-adherence to antidiabetic medication. The explanation could be that unemployed patients usually have enough free time and were thus more likely to remember to take their antidiabetic medication.
Mean HbA1c of those who were non adherent was 9.43%, their mean FBG was 10.01 Mmol/l, P = 0.01 and was signi cantly associated with antidiabetic medication non-adherence Limitations Due to Covid 19 pandemic, some patients were not comfortable with participating in research; this could have affected the quality of interaction and interview.
There was a challenge of space within the Diabetes mellitus clinic premise, with limited privacy during interviews. This could have compromised the privacy standards and thus impacted on the quality of patient responses.
Some study participants may have failed to recall accurately (recall bias) their previous experiences regarding adherence to their antidiabetic medication, thus ended up giving incomplete information that may have compromised study outcomes.

Strength of the study
Response rate was 100% which most likely gave a better estimate of the study outcome variables.

Conclusion
More than one third of the study participants were non-adherent to their antidiabetic medication, with medication expense being the most frequent reason mentioned for non-adherence to antidiabetic medication. Patients aged 60 years and above, and those having more than 5 years of disease since diagnosis, were 6.2 and 1.1 times more likely to be non-adherent to their antidiabetic medications.

Declarations
Ethics approval and consent to participate Voluntary recruitment was done and an informed consent was signed by study participants. Informed consent from study participants was obtained after full explanation of the details of the study to them in English and interpreted to local language (Runyankole) for those participants who did not understand English. Participants were not forced to enroll themselves if they did not want to. Study participants were also at liberty to withdraw from the study at any time as they wished without coercion or compromise of care they were entitled to. content; agreed to submit to the current journal; gave nal approval of the version to be published; and agreed to take responsibility for all aspects of the work.  Figure 1 Pie chart showing the level of antidiabetic medication non-adherence among participants in the Diabetes mellitus clinic at Mbarara Regional Referral Hospital from July to October 2020