Association of vitamin d with glycemic control in Saudi patients with type 2 diabetes: A retrospective chart review study in an emerging university hospital

Abstract Background Vitamin D (mainly 25‐hydroxyvitamin D, 25[OH]D) has stimulated increasing interest in Saudi Arabia over the current years due to its association with several different chronic diseases such as diabetes. This study aims to ascertain whether the vitamin D level has any influence on glycemic control in Saudi patients with type 2 diabetes (T2DM). Method This retrospective study included 200 patients with T2DM who visited Prince Sattam Bin Abdulaziz University Hospital between January 2015 and December 2015. Venous blood was collected and examined for “serum/plasma levels of 25(OH)D” and related variables using kit methods. HbA1C levels <7% and ≥7% were taken as indicators of good and poor glycemic control, respectively. An association between vitamin D deficiency and poor glycemic control was determined using multinomial logistic regression analysis. Results Among the total of 200 patients with type 2 diabetes, 118 (59%) were female and 82 (41%) were males with the mean age 42.4 ± 14.8 years. Good glycemic control (HbA1c < 7) was observed in 127 (63.5%), and poor glycemic control (HbA1c > 7) was found in 73(36.5%). The mean serum 25(OH)vit D was 20.27 ± 8.66 ng/mL, with (52% vs 82%; P ≤ .001) of subjects identified to have vitamin D deficiency in good and poor glycemic control groups, respectively. Conclusion Taken together, our results demonstrated an association of vitamin D level with poor glycemic control in patients with type 2 diabetes. However, additional studies with larger sample size from local population are warranted in future to confirm and extend the findings of the present study.


| INTRODUC TI ON
Diabetes is considered as a foremost public health epidemic worldwide that imposes a significant mortality and comorbidity attributable to macrovascular and microvascular complications. 1 Effective diabetes therapies have been proposed during the past few years.
While, novel insights to manage and prevent this condition remains necessary because of an amplified disease prevalence. Vitamin D has fascinated extensive interest in the past with respect to extraskeletal outcomes in several different disease conditions such as diabetes. 2 Deficiency of vitamin D (ie also referred to as serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is primarily prevalent in the diabetic population. [3][4][5] In King Saud Bin Abdulaziz University, the diabetes mellitus prevalence is estimated to be 23.7%. 6 World Health organization 7 reported diabetes to be 8.3% among the age group of 20 and 70 years that was considerably expected to intensify to 10.1% in 2035. A contemporary review on different Saudi Arabia population by Al-Daghri 8 suggested that deficiency of vitamin D prevalence studied from 2011-2016 was 81%. 8 Glycated hemoglobin (HbA1c) is one of the markers to analyze the glycemic state of an individual over several years. 9 At present, the levels of HbA1c are used to diagnose the diabetes and adjust therapies to manage diabetes. 10 The diagnosis of diabetes by HbA1c levels is advantageous over fasting blood glucose or glucose tolerance test because its levels are least affected by the changes in glucose concentrations in response to illness or stress. 10,11 Previous evidences from cross-sectional studies demonstrate an inverse relationship between hyperglycemia prevalence and vitamin D status. 4,12 Conversely, longitudinal studies show that low status of vitamin D is also a predictor for type 2 diabetes (T2DM) incidence. 13,14 Further clarity to whether vitamin D together with resistance from insulin is associated causally or whether they institute 2 autonomous features of patients with diabetes is needed. The findings from the previous interventional studies with the vitamin D supplementation have been contradictory. A meta-analysis and systematic review of fifteen studies examining the effects of Vitamin D supplementation concludes that presently, there lies an inadequate evidence about the beneficial effect in regard to recommending the supplementation of vitamin D as a foundation to improve insulin resistance and glycemia in patients with diabetes, normal fasting glucose, and impaired glucose tolerance. 15 A positive but weak vitamin D supplementation effect was observed on insulin resistance and fasting glucose in patients with diabetes. The inconsistency in these findings may be because several studies using a different supplementation regimen did not have glycemic control as a sole outcome and had lack of power or failed to include patients with diabetes.
Overall, the causality of the relationship between glycemic control and vitamin D in patients with diabetes has not been confirmed.
The poor status of vitamin D may play a critical role in T2DM development. However, only some prospective studies on the association and mechanism exist and how vitamin D affects the T2DM risk is specifically not clear. [16][17][18][19] Therefore, it is essential to explore whether the vitamin D levels have any influence on glycemic control in Saudi patients with T2DM diabetes. The study aims to determine the frequency of good and poor glycemic control and an association between vitamin D deficiency in addition to poor glycemia control among patients presenting with T2DM.

| Study design and settings
A retrospective study was undertaken at Prince Sattam Bin Abdulaziz University Hospital located in the city of Al Kharj, Saudi Arabia, between January 2015 and December 2015.

| Sampling technique/enrollment and patient selection
We used consecutive non-probability sampling design for recruit-

| Sample size
Sample size of 200 cases is calculated with 95% confidence level, 7% margin of error together with capturing expected percentage of poor glycemia control, that is, 65.2% among patients with T2DM.

| Data collection
The retrospective data were analyzed to identify patients having low vitamin D levels and those with poor and good glycemic control.
Blood samples were obtained from all the patients for baseline investigation retrospectively. The samples were drawn at the same time and sent to the hospital laboratory for blood analysis. These routine laboratory test samples were processed immediately. The measurements were documented from the hospital records retrospectively.
This included BMI, levels of vitamin D, fasting blood glucose, HbA1c, calcium, and creatinine levels in all patients. A Beckman Coulter AU analyzer was used to examine HbA1c.

| Selection of participants (Criteria for inclusion and exclusion)
Inclusion criteria enclosed T2DM patients, non-pregnant individuals, participants who did not receive any vitamin D supplementation during the past six months, and 18 years or older patients with diabetes who visited the outpatient clinics within the specified time.
Exclusion criteria include pregnant females, hospitalized patients, or individuals having chronic diseases such as liver disease, uremia, cancer, lung disease or Cushing syndrome or using any steroid medicines.

| Operational definition
The participants had diabetes if clinical history and fasting serum glucose concentration were > 126 mg/dL 19 mainly based on the guidelines of International diabetes federation. Participants who had vitamin D level less than 20 ng/mL were considered as having vitamin D deficiency. Participants were considered to have a glucose control if the HbA1c level was less than 7%. 1

| Data analysis
Data were evaluated using Statistical Package for Social Science (SPSS) software Version 23.0. Descriptive statistics that were obtained as frequencies and percentages were used for continuous variables. Independent sample t test was used for comparison. Chisquare test was applied to examine the association between different categorical variables. P-values < .05 were considered statistically significant. Multinomial logistic regression was used to estimate the strength of association between vitamin D deficiency and poor glycemic control. Data were stratified for the effect modifiers by using logistic regression.

| Ethical approval
The ethical approval was attained from the "Institutional Review Board University Hospital of Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia." A written informed consent was also obtained from all the participants. On comparison between the two groups of glycemic control,  Table 2 also demonstrated a significant inverse relationship between vitamin D deficiency and poor glycemic group.

| RE SULTS
The frequency of vitamin D deficiency was 63%, and insufficiency was 23%. Results revealed that vitamin D deficiency was higher in poor glycemic group [82% vs 52%; P ≤ .001 (χ 2 test)] as compared to controlled glycemic group. Table 3, multinomial logistic regression model analysis showed an association between the dependent variable, that is, 25(OH)D3 levels and the independent variable HbA1c (β: 0.300 [0.114-0.790]) which shows a significant increase in odds (70%) of having uncontrolled diabetes existing in patients with a vitamin D deficiency, which is also adjusted for age, gender, and BMI.

| D ISCUSS I ON
The objective of this study was to determine the association between vitamin D deficiency and poor glycemic control among T2DM patients. Diabetes mellitus is increasing globally and has posed severe health and financial threats. 20  Moreover, the females were found to have good glycemic control as compared with their male counterparts. The P-value was found the pancreatic β-cells. 30 Moreover, vitamin D tends to have anti-inflammatory and immunomodulatory effects that may limit peripheral insulin resistance by changing low-grade chronic inflammation. 10,11 Insulin sensitivity together with insulin secretion is equally considered to be calcium-dependent processes. Several cross-sectional studies have suggested an inverse association between blood vitamin D levels along with HbA1c not only in patients but also in normal adults. [31][32][33][34][35] Vitamin D deficiency has been reported worldwide and has affected around one billion population. 36 Its deficiency has been considered a potential risk factor for death in patients suffering from cardiovascular diseases and cancers. 36 Therefore, it is of great value to diagnose the deficiency at earlier stage and look for optimal remedial measures to avoid such complications. In Kingdom of Saudi Arabia, vitamin D deficiency is at rise along with increased incidence of diabetes. For example, in western region, 80% of the female population is reported to be vitamin D-deficient. 16 Similar results were found in eastern region of the country where even population was having sufficient dairy products and sun exposure. 37 In this context, the primary goal of this study was to measure and then correlate the

| CON CLUS ION
We conclude that the poor status of vitamin D may play a critical role in T2DM development. The population in Saudi Arabia is generally insufficient in 25OH vitamin D. We found an association of vitamin D level with poor glycemic control in patients with type 2 diabetes.
This association points toward the role of vitamin D supplementation along with raising awareness about hypovitaminosis D in the diabetic population that could possibly play a significant role in glycemic regulation in these patients.

| CLINIC AL IMPLI C ATI ON S AND RECOMMENDATI ON FOR FUTURE RE S E ARCH
Based on the results generated from our study, patients with T2DM having poor glycemic control should be screened regularly for deficiency of vitamin D in order to limit the burden of morbidity and mortality in Saudi Arabia. Patients with T2DM also having vitamin D deficiency should also be treated with vitamin D supplementation to improve indirect health-related outcomes. Further studies with larger sample size from local population as well as those on vitamin D supplementation in T2DM patients are needed in future, to confirm and extend the findings of the current study.

ACK N OWLED G M ENTS
The authors are thankful to all the participants and the hospital staff (technicians and nurses) who helped us during data collection.

AUTH O R CO NTR I B UTI O N S
KKA designed the study. GA, AA, NA, MBS, MA, DA, FBH, and AAQ performed data acquisition. KKA and SA performed the data analysis, and HAR drafted the study. All authors read and approved the final study for submission.

E TH I C A L A PPROVA L
The study was approved by the "Institutional Review Board University Hospital of Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia." All analytical tests/procedures performed in this study were in accordance with the ethical standards of the institutional research committee and in accordance with the 1964 Helsinki declaration and its amendments. Informed consent was obtained from all individual participants included in the study."

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.