Inadequate Control of Diabetes and Metabolic Indices Among Diabetic Patients: A Population Based Study from the Kerman Coronary Artery Disease Risk Study (KERCADRS)

Background: The goal of diabetes control should be feasible in order to minimize the risk of its adverse events and to reduce its burden and cost on patients. The current study aimed to assess the status of glycemic control in male and female patients with Type 2 Diabetes Mellitus (T2DM) in Kerman, Iran. Methods: In the present study, 500 T2DM (300 women and 200 men) from the Kerman Coronary Artery Disease Risk Study (KERCADRS), a population-based study from 2009 to 2011, were selected. Patients were >18 years old, had Fasting Blood Sugar (FBS) higher than 126 mg/dl, and had been through treatment for their diagnosed disease. All participants underwent Glycosylated Hemoglobin (HbA1c) analysis. HbA1c less than 7% was considered as good glucose control. Other metabolic indices based on American Diabetes Association (ADA) target recommendations were considered. Results: The mean level of HbA1c in total subjects was 8.56 ± 4.72% that only 31.66% of men and 26.00% of women had controlled level of HbA1c. Total cholesterol less than 200 mg/dl was reported in 64.50% of men and 44.00% of women, High Density Lipoprotein (HDL) more than 40 mg/dl was revealed in 20.50% of men and 34.67% of women, and Low Density Lipoprotein (LDL) less than 100 mg/dl was reported in 41.50% of men and 25.33% of women. In multivariate logistic regression model, longer duration of disease and higher Waist Circumference (WC) were positively associated with uncontrolled diabetes status. Conclusion: The findings of the present study revealed that diabetes control in T2DM was inadequate. Changing the policy of treatment in individual patient and establishing better diabetes clinic to decrease the frequency of uncontrolled T2DM are crucial. Paying attention to other affecting metabolic components such as WC in the process of T2DM management is important.


Implications for policy makers
Given the role of diabetes as an important health related problem in the community, appropriate policies and implementing up-to-date guidelines to better control this disease are unavoidable. • Diabetes Mellitus (DM) is a complex disease which is correlated with other components of cardiovascular risk factors. So, the assessment of other risk factors like dietary pattern, and metabolic risk factors as well as two factors of Waist Circumference (WC) and the duration of the disease (which revealed the most important factors of inadequate control of Type 2 Diabetes Mellitus (T2DM) in the present study) should be considered in the process of the follow-ups of the patients to reach and achieve the treatment goals of HbA1c <7%. Therefore, more effective management of the disease might be required.

Implications for public
In the present study, we found that the diabetes control was not adequate. However, the patients should realize that in most cases the inadequate diabetes control can have several causes such as: irregular use of medication, disregarding physician's recommendations to modify or change the trend of treatment in the course of disease, not paying enough attention to the role of nutrition, exercise/physical activity and weight loss in treatment program. Through making changes in the lifestyle of the public, the chance of controlling Type 2 Diabetes Mellitus (T2DM) can be considerably increased; consequently the probability of occurrence of other related diseases can be decreased. These simple (in theory) but difficult (in practice) tasks can be effective in preventing or delaying the onset of type 2 diabetes.
(WHO) in 2000, about 170 million people suffered from diabetes worldwide and the number will be doubled by 2030 (3). Because of diabetes-related macrovascular, microvascular and neuropathic complications, a tight and consistent glycemic control can result lower complications and preventing its life-threatening events (4,5). The goal for glycemic control should be feasible to minimize risk for adverse events and reduce load of complications and cost on patients (6,7). Glycosylated Hemoglobin (HbA1c) index has become the gold standard for long-term monitoring glycemic control and is a validated measurement tool for assessing diabetes status. A HbA1c level 6.5% or less has been suggested as controlled Diabetes Mellitus (DM) (8-10). The HbA1c goal for diabetic patients has been generally considered less than 7%, however recent guidelines have emphasized on more stringent goals, such as a normal HbA1c value of less than 6% especially in individual patients if they are achievable without significant hypoglycemia (11). It has been suggested that each percentage point increase in HbA1c results in a 10% increase in mortality from all forms of coronary heart disease and brain stroke (12). Diabetes is a common non-communicable disease among Iranian population with a prevalence of 7.7% in the middleage group and with poor quality of care expected for eye examination (13,14). In 2002, more than 100,000 deaths were recorded as a consequence of diabetes in our country (15). Even, it is now more likely to be expanded earlier among children and teenagers so that a fasting blood glucose of more than 100 mg/dl has been detected in 4.1% of Iranian schoolage children and adolescents with the maximum prevalence between ages 10 and 14 (16). While, the prevalence of diabetes in 25 to 64 years old Iranian adults has been estimated to be 7.7%, corresponding to about two million adults that only half of them are diagnosed (17,18). In addition, the status of diabetes control in different urban and rural areas in our country has been already unknown and a few epidemiologicalbased studies have been conducted to identify trend of the diabetic control in our clinical settings. The present study was undertaken to assess the status of glycemic control and compare this index between male and female patients with T2DM by measurement of HbA1c in Kerman, the largest province in Iran, through a population-based study.

Participants
The Kerman Coronary Artery Disease Risk Study (KERCADRS) is a population-based, epidemiological research among a cohort of 5,900 individuals (3,238 women) aged between 15 to 75 years (from 2009 to 2011) and residence in Kerman city addressing the information of the risk profile of coronary artery disease including serum lipids, physical activity, alcohol and drugs addiction, mental disorders like stress and depression, hypertension as well as dietary regimens. The participants had been recruited through a household survey by non-proportional to the size one-stage cluster sampling. Non-communicable risk factors were collected by both a structured questionnaire (such as cigarette and opium smoking, obesity, hypertension, and so on) and laboratory measurements (such as HbA1C, Fasting Blood Sugar (FBS) and lipid profiles). Interviews were done by trained internal specialist, general practitioners, nurses and trained interviewers. [The methodology of this research has been published elsewhere] (19).
The participants of the current study were those diabetic patients with inclusion criteria of being older than 18 years, had FBS higher than 126 mg/dl, and under treatment for their diagnosed disease. Additional information in regard to the epidemiology of diabetes, pre-diabetes, diagnosed and undiagnosed diabetes for the KERCADR study has been already published (20). All subjects were identified as having diabetes and/or using any hypoglycemic medication at the time of their recruitment into the study. Those with malignant disease, severe renal insufficiency, cirrhosis, active liver disease attributable to viral infection and/or other acute infectious or inflammatory disorders were all excluded.

Clinical and biochemical examinations
Participants underwent a biochemical examination that included measurement of HbA1c, fasting glucose, systolic and diastolic blood pressure, serum triglyceride, and total, Low Density Lipoprotein (LDL), and High Density Lipoprotein (HDL) cholesterol. We examined weight and standing height expressed as Body Mass Index (BMI) (weight in kilograms divided by height in meters squared). The Waist Circumference (WC) was measured in a horizontal plane, midway between the inferior margin of the ribs and the superior border of the iliac crest. Blood pressure was recorded using an automatic oscillometric blood pressure recorder after at least 5 min of rest in a chair and arm supported at heart level. For biochemical analysis, blood samples of 5 ml were drawn after 12 h overnight fasting for measuring lipid profile, FBS, and HbA1c. Plasma glucose was measured using the glucose oxidase peroxidase method. The level of serum lipid profile was also determined by standard enzymatic procedures. The primary indicator of glycemic control was level of HbA1c based on Biorad Variant High Performance Liquid Chromatography [HPLC] assay. This measure integrates control over the prior 12 weeks. In clinical practice, the goal for good control is HbA1c <7%, although it may be as low as 6.5% in the absence of hypoglycemia or risk factors for hypoglycemia, as mentioned already (7). In the present study, controlled T2DM was considered as HbA1c <7%.

Statistical analysis
Results were presented as Mean ± Standard Deviation (SD) for quantitative variables and were summarized by absolute frequencies and percentages for categorical variables. Categorical variables were compared using Chi-Square test or Fisher's exact test when more than 20% of cells with expected count of less than 5 were observed. Quantitative variables were also compared using T-Test or One-way analysis of variance (ANOVA) test. Multivariate logistic regression analysis was used to determine indicators of uncontrolled diabetes status adjusted for age, gender and diagnostic criteria. Statistical significance was determined as a P< 0.05. All statistical analysis was performed using SPSS 20.0 (SPSS Inc., Chicago, Illinois). Table 1 shows the baseline men and women characteristics. There were more females (60.00%) than males (40.00%).     Table 4. Those with lower total triglyceride level (less than 150 mg/dl) had lower mean HbA1c value (7.94%) than those with higher total triglyceride levels (9.02%). Also, mean HbA1c level was lower in patients with LDL level lower than 100 mg/dl (8.08%) compared to those with higher LDL level (8.77%). On the other hand, the main indicators of uncontrolled diabetes according to HbA1c values were high triglyceride and LDL levels. In multivariate logistic regression model adjusted for background parameters (Table 5), higher duration of disease and higher WC were positively associated with uncontrolled diabetes status. However, higher lipid profile levels or medications for controlling diabetes could not predict uncontrolled diabetes status.

Discussion
The  (27). The findings of a recent multicenter, cross-sectional survey of outpatients carried out in 606 hospital in all provinces of China among more than 230 thousands T2DM demonstrated that less than one third of the patients achieved the goal of HbA1c less than 7% (28). Regarding associated indicators of poor controlled diabetes, we evaluated some clinical criteria and found that only higher duration of disease and higher WSs were associated with this poor diabetes controlling. However, we did not  consider socio-economic characteristics for this aim that might be powerful indicators. On the other hand, the most important factor associated with poor control diabetes status can be some clinical risk profiles including central obesity and disease duration, however potential effects of some other determinants such as inadequate knowledge of patients and even care providers should not be ignored. According to some surveys, lack of adequate knowledge about the disease is a principle affecting factor. In this regard, in a study among Pakistani diabetic population, 58% of the patients lacked appropriate education for disease management that also had the highest levels of HbA1c of 9.98% (29). Another main factors pointed in other studies was financial burden imposed on the patients accounts for the majority of the patients with suboptimum HbA1c levels. Inaccessibility to healthcare facilities, psychosocial influences, low level of self-care, and no adherence to treatment are other limiting factors for developing countries (30)(31)(32)(33).
Regarding association between obesity (high WC) and poor diabetes control, it has been suggested that adults with insulin dependent diabetes are often obese, and this may adversely affect their diabetic control, resulting in complications (34). WC alone has been identified as a strong determinant for glucose exacerbation and glycemic relapse among people with T2DM and more predictive than other components of metabolic syndrome (35), although BMI was also another powerful predictor of insulin resistance (36) and poor control of diabetes. Blaha et al. (35) showed that WC had a positive significant correlation with increased risk of hyperglycemic recurrence in both simple analysis (hazard ratio: 3.4) and multivariate analysis (hazard ratio: 3.2). Such findings was recognized in a study by Janiszewski et al. (37), which in a cross-sectional study among around 6,000 individuals from the U.S. showed that WC was significantly considered as a major predictor of blood glucose levels. Obesity along with other risk factors such as physical inactivity and unsound diet regime have been known as significant determinants of insulin resistance and beta-cell failure (as physiologic factors), which can consequently lead to inadequate T2DM control (38). We found a direct association between poor diabetes control and disease duration. Similarly, Otiniano et al. (39) found that subjects with poor control had longer disease duration, had lower education, used the glucometer more frequently, and had more diabetes-complications when compared to those in the good glycemic control group. In the multivariable analysis, longer disease duration besides low educational level, foreign-born, smoking, obesity, daily glucometer use, and having macro-complications were main determinants of poor diabetes control. Study by Longo-Mbenz et al. (40) duration diabetes ≥4 years was significantly associated with the presence of diabetic complications and its inappropriate controlling. In a study in Jordan among patients with T2DM, it was shown two factors of longer duration of DM and poor adherence to behaviors related to self-care management were significantly (in the multivariate analysis) associated with inadequate control of DM, which around two third of the T2DM patients had HbA1c ≥7% (41). Our results were consistent with the findings of these studies. It has been studied that advanced age and duration of diabetes have a significant association with increased likelihood of insulin resistance and levels of HbA1c (42). It is determined that aging and longer duration of diabetes are significant predictors of uncontrolled HbA1c which may lead to chronic hyperglycemic and insulin insensitivity (43). The main cause of this association might be related to more highlighted effect of longer diabetes duration and higher prevalence of other diabetes disease risk factors such as hyperlipidemia as well as complication of disease that can potentially result in more severe disease status and more severe disease control. Although we did not obtain any relationship between poor glycemic control and type of treatment approach of diabetes, some authors showed that the subgroup of patients not treated with insulin presented relatively lower rates of poor glycemic control, while those with type 2 diabetes using insulin had a prevalence of inadequate glycemic control. One survey by Arai et al. (44) in Japan and another study by Yu et al. (45) in Taiwan also reported lower mean levels of HbA1c among patients not requiring insulin. These differences changed after stratifying the data by diabetes duration, but even among patients at earlier stage of diabetes (<5 years duration) insulin treatment was associated with worse control when compared to diet alone or combined with oral treatment, possibly due to more severe and more difficult to control diabetes in the former patients. We found no significant difference in glycemic control by gender. Several studies have failed to show significant gender differences related to self-care and control of diabetes (46)(47)(48)(49). Contrarily, in a study in a Pakistani Muslim diabetic population in UK, women were worse than men in performing regular glucose measurements, in managing persistent hyperglycemia, and had also poorer glycemic control overall (HbA1c 8.8% vs. 8.1%, P< 0.05) (50). Results from a survey in Mexico have suggested that women have several social disadvantages, deterioration of healthy life, poor self-care and lack of solidarity that increases their vulnerability to reach glycemic control successfully (51).

Strengths and limitations
The distinctive strengths of this study are the large provincial sample, the data collection by trained and certified interviewers from general practitioners not part of the local center staff, and the measurement of HbA1c by a reliable method in a single central laboratory. Despite that, one limitation is that the study did not assess most of socioeconomic factors for determining indicators of poor diabetes control such as their education level, income, level of physical activity, and dietary habits.

Conclusion
Diabetes control in these Kermanian diabetic patients is not adequate as shown by very high rates of poor control of HbA1c, because of poor diabetes care and management. Longer diabetes duration and obesity are significantly associated with poor control of diabetes.
University of Medical Sciences (KMU). The authors would like to thank all subjects who participated in this study and all interviewers and colleagues who helped us to collect the data.