Patient-Related Determinants of Glycaemic Control in People with Type 2 Diabetes in the Gulf Cooperation Council Countries: A Systematic Review

The aim of this systematic review is to assess patient-related factors affecting glycaemic control among people with type 2 diabetes in the Arabian Gulf Council countries. MEDLINE, Embase, PsycINFO, CINAHL, and Cochrane CENTRAL databases were searched from their date of inception to May 2016. Two researchers independently identified eligible studies and assessed the risk of bias. A total of 13 studies met the inclusion criteria. One study was population based, six recruited participants from multiple centres, and the remaining were single centred. The majority of the studies were of low to moderate quality. Factors associated with poor glycaemic control include longer duration of diabetes, low level of education, poor compliance to diet and medication, poor attitude towards the disease, poor self-management behaviour, anxiety, depression, renal impairment, hypertension, and dyslipidaemia. Healthcare providers should be aware of these factors and provide appropriate education and care especially for those who have poor glycaemic control. Innovative educational programs should be implemented in the healthcare systems to improve patient compliance and practices. A variation in the results of the included studies was observed, and some potentially important risk factors such as dietary habits, physical activity, family support, and cognitive function were not adequately addressed. Further research is needed in this area.


Introduction
Diabetes mellitus is one of the major public health issues of the 21st century [1][2][3]. Globally, 8.8% (415 million) of adults suffered from diabetes in 2015, and it is estimated that 652 million people (10.4%) will have diabetes by 2040 [2]. The World Health Organization (WHO) reported that high blood glucose level due to diabetes is the third highest risk factor for premature mortality after high blood pressure and tobacco use [4]. Diabetes is attributed to 14.5% of all-cause mortality among adults, and half of these deaths occur in adults under the age of 60 years [2]. Nonetheless, diabetic complications are a major cause of disability and reduced quality of life. The estimated total global health expenditure due to diabetes is $673 billion in 2015, and it will reach $802 billion in 2030 [2].
A recent International Diabetes Federation (IDF) report suggests that the Middle East and North Africa regions, which include the Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates (UAE)), have the highest prevalence of diabetes (10.7%) in the world next to North America and the Caribbean region (11.5%) [2]. An estimated 35.4

million adults in the Middle East and North
Africa regions had diabetes in 2015, of whom over 40.6% were undiagnosed [2]. The number of people with diabetes in this region is anticipated to reach 72.1 million by 2040 [2]. The GCC countries share boundaries and similar climates, cultures, lifestyles, and economic development. These countries are among those with the highest prevalence of diabetes in the Middle East and North Africa regions and globally, with the prevalence of the disease ranging from 14.8% (Oman) to 20% (Saudi Arabia, Kuwait, and Qatar) [2].
Diabetes management involves strictly maintaining a person's blood glucose level close to the normal range. There is a strong relationship between an elevated blood glucose level and the risk of complications and mortality in people with diabetes [5,6]. Poor glycaemic control is defined as a glycated haemoglobin (HbA1c) equal to or above 7% or a fasting plasma sugar (FPS) above 7.2 mmol/l for adults who are not pregnant [7]. Poor glycaemic control (HbA1c > 7%) among people with type 2 diabetes mellitus (T2DM) in the GCC countries is common, ranging between 59% and 70.7% in Saudi Arabia [8,9], 68% and 69% in the UAE [10,11], 86.5% and 88.8% in Bahrain [12,13], and 54% and 65% in Oman [14,15], while a study reported that 55% of people with T2DM in Kuwait have HbA1c > 9% [16].
A number of studies have assessed factors associated with poor glycaemic control among people with T2DM in GCC countries sporadically. A systematic approach is needed to summarise their findings in order to identify gaps in the literature and provide guidelines for future research. Thus, the aim of this systematic review is to assess patient-related factors that affect glycaemic control among people with type 2 diabetes in the GCC countries.
2.2. Selection of Studies. Two reviewers (MJA and AA) independently screened the retrieved articles by title, then by abstract, and finally by reviewing the full text of eligible articles. Any disagreement between the two reviewers was resolved by discussion with a third reviewer (BB).

Studies Inclusion and Selection
Criteria. All observational studies that examined the effect of patient-related factors affecting glycaemic control among adults with T2DM living in the GCC countries were considered for inclusion. Because the majority of people in the GCC countries have T2DM, studies that assessed the level of control among people with diabetes in general (types 1 and 2) were included. Studies were excluded if they did not include adults with T2DM, if the sample was recruited from outside of the GCC countries, and/or if the study did not examine the association between patient-related factors and glycaemic control. Studies that focused only on type 1 diabetes, children with T2DM, gestational diabetes, or adults with impaired glucose tolerance or impaired fasting glucose were excluded. Studies investigating the effectiveness of antidiabetic medications only were also excluded. In addition, articles were excluded if they were reviews or conference presentations.

Data Extraction.
Two reviewers (MJA and AA) independently extracted the data using a data extraction form. The extracted data include the first author, the year of publication, the name of the country, the sampled population, the number of participants, participants' gender, participants' age, the method of assessing glycaemic control, the data collection tool, the risk factors investigated, and the factors found to be associated with glycaemic control.
2.5. Assessment of Quality. Two reviewers (MJA and AA) independently assessed the risk of bias of the included studies using the National Heart Lung and Blood Institute (NHLBI) quality assessment tool for observational studies (Tables 1  and 2) [17]. The tool assesses the internal validity and risk of bias using 14 criteria for cohort and cross-sectional studies and 12 criteria for case-control studies. Each criterion was rated as "yes," "no," "cannot determine," "not applicable," or "not reported." An overall judgment of the quality of the study was then rated as high (low risk of bias), fair (moderate risk of bias), or low (high risk of bias). Any disagreement between the two reviewers regarding the assessment of risk of bias was settled by discussion. Figure 1 shows a flow chart of the search results and the number of studies included in this review. A total of 1788 articles were retrieved from the five databases (MEDLINE = 460, Embase = 1076, PsycINFO = 10, CINAHL = 149, and Cochrane = 93). After the removal of duplicates, 1211 articles remained. After having screened article titles and abstracts, 1161 articles were removed as these were letters, editorials, case reports, review articles, animal/cell studies, not from the GCC countries, did not include adult participants with T2DM, did not cover glycaemic control, or did not assess factors affecting glycaemic control. Thus, 50 full-text articles were screened for further eligibility. Of these 50 articles, 37 articles were excluded. Eight articles did not evaluate glycaemic control, four studies were not conducted in the GCC countries, one study did not include people with T2DM, and 16 did not evaluate patientrelated factors affecting glycaemic control. In addition, eight articles were conference papers and were therefore excluded. A total of 13 studies met the inclusion criteria of this review.

Criteria
Yes No Others (CD, NR, and NA) * (1) Was the research question or objective in this paper clearly stated?
(2) Was the study population clearly specified and defined?
(3) Was the participation rate of eligible persons at least 50%? (4) Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? (5) Was a sample size justification, power description, or variance and effect estimates provided? (6) For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? (7) Was the time frame sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? (8) For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure or exposure measured as continuous variable)? (9) Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? (10) Was the exposure(s) assessed more than once over time? (11) Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? (12) Were the outcome assessors blinded to the exposure status of participants? (13) Was loss to follow-up after baseline 20% or less? (14) Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?

Key
The association between gender and glycaemic control was evaluated in 10 studies. Of these, one study reported that female gender was associated with poor glycaemic control compared to male gender (adjusted OR: 2.84, p value <0.05) [21]. In contrast, Al-Lawati et al. showed that female gender was associated with good glycaemic control (adjusted OR: 1.5, p value: 0.001) [22]. No association was found between gender and glycaemic control in the other eight studies [8,10,11,14,15,18,20,24].
Three out of eight studies that assessed the association between the duration of diabetes and glycaemic control have found an association. Binhemd et al. have reported a positive correlation between the duration and HbA1c level (p < 0 001) [19]. In the study by Al-Lawati et al., the adjusted OR of good glycaemic control for people with a duration of diabetes ≥5 years was 0.8 (p value: 0.041) compared to those with a duration of <5 years [22]. D'Souza et al. reported that the people with poor control were 49.1%, 52.8%, and 70.5% for diabetes duration groups 0-9 years, 10-19 years, and ≥20 years, respectively Table 2: Quality assessment of case-control studies.

Criteria
Yes No Others (CD, NR, and NA) * (1) Was the research question or objective in this paper clearly stated and appropriate?
(2) Was the study population clearly specified and defined?
(3) Did the authors include a sample size justification? (4) Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same time frame)? (5) Were the definitions, inclusion and exclusion criteria, algorithms, or processes used to identify or select cases and controls valid, reliable, and implemented consistently across all study participants? (6) Were the cases clearly defined and differentiated from controls? (7) If less than 100 percent of eligible cases and/or controls were selected for the study, were the cases and/or controls randomly selected from those eligible? (8) Was there use of concurrent controls? (9) Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a participant as a case? (10) Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study participants? (11) Were the assessors of exposure/risk blinded to the case or control status of participants? (12) Were key potential confounding variables measured and adjusted statistically in the analyses?
If matching was used, did the investigators account for matching during study analysis?
Quality rating (good, fair, or poor) (see guidance) Rater no. 1 initials: Rater no. 2 initials: Additional comments (if poor, please state why): * CD: cannot determine; NA: not applicable; NR: not reported.
Two studies assessed the effect of family history of diabetes on glycaemic control. In one study, no significant association was found [21]. Meanwhile, in the other study, a family history of diabetes was found to be associated with lower risk of poor glycaemic control (OR: 0.39, p value: 0.001) [24]. This study also assessed the effect of ethnicity on glycaemic control, but no association was found.

Modifiable Factors.
A number of modifiable factors were found to be associated with glycaemic control. Binhemd et al. reported a negative correlation between HbA1c and patient compliance to management as well as the attitude towards the disease (p value < 0.001 and 0.01, resp.) [19]. Al-Hayek et al. showed that compared to participants with HbA1c < 7%, those with HbA1c ≥ 7% had lower mean score of adherence to medication (5.4 ± 1.2 compared to 7.4 ± 1.4, p value < 0.001), higher mean score of anxiety (10.3 ± 1.7 compared to 7.9 ± 1.3, p value < 0.001), and higher mean score of depression (9.8 ± 1.3 compared to 6.9 ± 0.9, p value < 0.001) [8]. Malik et al. found that individuals who were followed up in primary healthcare centres were more likely to have poor glycaemic control (OR: 2.4, p value: 0.001) compared to those who were followed up in hospital [24]. Al-Kaabi et al. reported that the number of carbonated drinks (sugar sweetened and sugar free) consumed was positively associated with HbA1c level (adjusted beta coefficient: 0.20, p value: 0.029) [10]. Shamsi et al. showed that the mean HbA1c level increases progressively from 5.97% ± 1.34% for those with very good dietary practice to 10.95% ± 1.6% for those with very poor dietary practice (p value: 0.006) [25]. Al-Lawati et al. reported that compared to estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m 2 , the OR of good glycaemic control was 1.9 (p value 0.013) for those who have eGFR ≥ 60 ml/min/1.73 m 2 [22]. Al Balushi et al. showed that compared to participants with HbA1c ≤ 7%, those with HbA1c > 7% had higher mean diastolic blood pressure (84 ± 9 mmHg compared to 80 ± 8 mmHg, p value: 0.006), higher total cholesterol (5.2 ± 1.3 mmol/l compared to 4.7 ± 0.8 mmol/l, p value: 0.002), and higher low-density lipoprotein (LDL) (3.8 ± 1.0 mmol/l compared to 3.0 ± 1.2 mmol/l, p value: 0.38) [14]. D'Souza et al. reported that a large proportion of those who completed diploma/technical degree had poor glycaemic control (67.4%) compared to those who completed high school (45.7%) and lower than high school (52.1%) (p value < 0.001) [15]. Two other studies did not find an association between education level and glycaemic control [10,11]. The study by D'Souza et al. has also reported that patient perception of empowerment for self-management increased the likelihood of good glycaemic control (beta coefficient: 0.66, p value 0.001) [15].        In regard to the effect of modality of treatment on glycaemic control, Al-Nuaim et al. found that compared to participants on diet regimen, only the adjusted OR of poor control was 1.65 and 2.64, respectively, for those on oral agent and insulin [20]. Similarly, Al-Lawati et al. reported that the likelihood of good control was lower for those on oral agent (adjusted OR: 0.2, p value: 0.001) and for those on insulin (adjusted OR: 0.1, p value: 0.001) compared to diet regimen only [22]. Ajabnoor et al. reported, however, that participants on insulin had lower mean HbA1c (14.3 ± 1.0) compared to diet only (16.3 ± 1.8) and oral agent (17.0 ± 0.0) (p value < 0.001) [18].

Discussion
This systematic review summarises patient-related factors affecting glycaemic control among adults with T2DM in the GCC countries. Using a reproducible search strategy and prespecified inclusion/exclusion criteria, we identified 13 articles for inclusion in this review. The quality of the included studies is low to moderate in general, and the effect of some potentially important risk factors (including diet, physical activity, family support, and cognitive impairment) was not adequately investigated.
One cross-sectional study reported that age was associated with poor glycaemic control [15]. With advancing age, there might be a waning of the function of the β-cells of the pancreas, and some people develop other comorbidities that may affect glycaemic control. Similar to the findings of a previous systematic review [26], however, two of the included studies have found that elderly people with diabetes had better glycaemic control than young people [10,22]. Elderly people are more likely to adhere to the management plan compared to young people who are more likely to be affected by the change in lifestyle and urbanisation [22,27].
The duration of the disease is another important nonmodifiable risk factor of poor glycaemic control that was identified in three cross-sectional studies [15,19,22]. With longer duration of diabetes, the function of the pancreas further deteriorates because of the failure of the β-cells [28]. In addition, individuals with longer duration of diabetes are at a higher risk of developing diabetes-related complications, which can have a substantial effect on glycaemic control. With regard to the effect of gender on glycaemic control, two cross-sectional studies found an association but with contradicting results. One study reported that female gender was associated with poor glycaemic control [21], while another reported that females had better glycaemic control compared to males [22]. The inconsistency in the results of these studies may be explained in part by a variation in the methodology and heterogeneity between patients across the study population. In the systematic review undertaken by Sanal et al., however, it was found that the female gender was a risk of poor glycaemic control [26].
Compliance to diabetes management including adherence to diet, physical activity, medications, and self-monitoring of blood sugar is crucial in the management of diabetes. This current review shows that compliance to management and adherence to medications were significantly associated with good glycaemic control [19]. There is a gap in the knowledge, however, regarding barriers to compliance and adherence to management for people with diabetes in the GCC countries.
Two recent studies included in this review have found that compared to people with diet regimen only, those who were on oral agent and insulin had higher risk of poor control after adjustment for other risk factors [20,22]. These findings may emphasize the potentially important role of lifestyle modification on the glycaemic control. In this review, however, we have found that the effect of lifestyle factors, including dietary habit and physical activity, on glycaemic control has not been studied adequately in the context of the GCC countries. Well-planned healthy eating habits with the supervision of a dietician can reduce HbA1c by 0.5 to 2.0% for people with T2DM [29][30][31][32]. There is also strong evidence of the effect of regular exercise on lowering HbA1c for people with T2DM [33][34][35]. Of the 13 studies included in this review, only two cross-sectional studies explored the association between dietary habits and glycaemic control [10,25]. One study that assessed the association between various dietary practices and glycaemic control reported that consumption of carbonated (soda) drinks was the only associated factor [10]. The other study showed that participants who followed healthier dietary practices had a lower mean HbA1c [25]. Similarly, only two studies evaluated the association between physical activity and glycaemic control and reported no association [11]. In the latter four studies [10,11,25], however, the recruited sample was relatively small, no adjustment for confounders was done in most of them [11,25], and the majority were of low to moderate [10,25] quality.
Other modifiable risk factors that were found to be associated with glycaemic control in this review include patients' attitude to diabetes, the location of scheduled follow-up visits (hospital or primary healthcare centres), eGFR, anxiety, depression, diastolic blood pressure level, cholesterol level, LDL level, and patient empowerment for self-management [10,14,15,19,22,24]. Studies included in this review, however, have assessed different sets of these risk factors; hence, a comparison of their findings was not possible.
In the GCC countries, wives are usually responsible for preparing meals for the whole family, including members with diabetes. For cultural reasons, on the other hand, some women prefer to be accompanied by a relative when they go out for exercise or when they visit healthcare centres. Therefore, it is likely that family support has an important role in the management of diabetes, which should be taken into account when evaluating glycaemic control. This is supported by the results of a systematic review showing a potential importance role of family support in the management of T2DM [36]. In addition, poorly controlled diabetes has been associated with a decline in cognitive function [37,38], and impaired cognitve function is likely to have a negative effect on glycaemic control. That is because people with impaired cognition is less likely to be compliant to diabetes treatment plan.
Family support and cognitive function are potentially important risk factors for glycaemic control, which have not been explored in any of the included studies in this systematic review. Thus, the relationship of these factors with control needs a comprehensive investigation in future studies. Further, some of the modifiable risk factors such as the attitude towards the disease, barriers to compliance, anxiety, depression, and patient empowerment were not addressed adequately; hence, they need re-evaluation to build a stronger evidence. Future researchers should also reassess the association between glycaemic control and lifestyle factors using methodologically sound study design.
The strength of this review lies in the systematic, comprehensive, and unbiased approach taken during the literature search, data extraction, and assessment of the risk of bias. As the identified studies were either cross-sectional or casecontrol studies, a causal relationship between the risk factors and glycaemic control cannot be established. Moreover, because the studies in this review used different statistical methods, it was neither possible to generalise the magnitude of the effect of risk factors on glycaemic control nor possible to conduct a meta-analysis.
No studies assessing the factors affecting glycaemic control in Qatar or Kuwait were identified. Nevertheless, the results of this systematic review can be useful to all of the GCC countries. The populations of the GCC countries share similar cultures and lifestyles, and the healthcare services and medications are free of charge to all citizens.

Conclusion
This systematic review identified the following variables as the risk factors for poor glycaemic control in the GCC countries: low level of education, longer duration of diabetes, poor compliance to diet and medication, poor attitude towards the disease, poor self-management behaviour, anxiety, depression, renal impairment, hypertension, and dyslipidaemia. The policymakers should introduce large-scale awareness program and educational models to improve patient compliance and practices and to support patient empowerment for self-management. Healthcare providers should be aware of these risk factors and provide optimal care and guidelines for enriching self-management of the disease. The existing studies from the GCC have heterogeneity in their methodology, which may be related to the variation in their findings. In addition, some risk factors that may affect glycaemic control such as lifestyle, social support, and cognitive function have not been investigated adequately. Future research should address these issues.