IS HEMOGLOBIN A1C A VALUABLE PARAMETER IN NON-DIABETIC PATIENTS WITH PERIPHE- RAL ARTERIAL DISEASE?

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1 Acta Medica Mediterranea, 2016, 32: 911 IS HEMOGLOBIN A1C A VALUABLE PARAMETER IN NON-DIABETIC PATIENTS WITH PERIPHE- RAL ARTERIAL DISEASE? MEHMET UGUR ES 1, SEFA SENOL 2,*, AHMET YUKSEL 3 1 Department of Cardiovascular Surgery, Medicalpark Tokat Hospital, Tokat, Turkey - 2 Department of Cardiovascular Surgery, Elazig Education and Research Hospital, Elazig, Turkey - 3 Department of Cardiovascular Surgery, Bingol State Hospital, Bingol, Turkey ABSTRACT Introduction: The aim of this study was to investigate the value of hemoglobin A1c (HbA1c) levels in patients with peripheral arterial disease (PAD) who had not been diagnosed with diabetes mellitus (DM). Materials and methods: This prospective study was performed on a total of 224 participants between June 2013 and June The participants were divided into two groups, as follows: Group 1 (PAD group) included 112 patients with PAD (mean age: 57±12 years, 84 males) without a diagnosis of DM, while Group 2 (control group) included 112 participants (mean age: 54±11 years, 80 males) with normal physical examination results and normal duplex ultrasonography findings when examined for PAD. The groups were compared according to the clinical and demographic characteristics, levels of some biochemical parameters, and particularly HbA1c levels. Thus, the importance of HbA1c levels in patients with PAD was investigated. Results: The proportions of hypertension, smoking, family history of DM, and fasting glucose levels were significantly higher in PAD group. The groups were statistically similar in terms of levels of total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, triglyceride, urea and creatinine. In PAD group, the average HbA1c level was significantly higher than in control group. Conclusion: Routine screening of HbA1c in patients with PAD would be useful for the early diagnosis of prediabetes and DM, as well as for the prevention of the potential complications of DM. Key words: Hemoglobin A1c, peripheral arterial disease, diabetes mellitus, prediabetes. DOI: / _2016_4_109 Received January 30, 2016; Accepted June 02, 2016 Introduction Peripheral arterial disease (PAD) has a high prevalence and morbidity rate in adult population. Its general prevalence is approximately 3-10%, and this may increase up to 15-20% in patients over 70 years of age (1,2). Endothelial dysfunction, platelet and smooth muscle cell dysfunction, and a state of hypercoagulability may be related to atherosclerosis and hyperglycemia (3). It is known that the patients with diabetic PAD exhibit high mortality and morbidity in terms of cardiovascular diseases (4). Hemoglobin A1c (HbA1c) measurement is recommended for clinical diabetes mellitus (DM) screening (5). HbA1c, which reflects the blood glucose concentrations for the previous 8-12 weeks, is a consistent predictor of long-term blood glucose control. Numerous clinical studies and meta-analysis in the literature have shown the diagnostic and prognostic value of the glycosylated HBA1c among prediabetic and diabetic patients. In addition, it has been demonstrated that HbA1c is both sensitive and specific in the determination of undiagnosed DM cases (6,7). Type 2 diabetes is a major health problem that has emerged worldwide as an important cause of morbidity and mortality (8). According to a report by the International Diabetes Federation, 246 million people are affected by this disease, and it is estimat-

2 912 Mehmet Ugur Es, Sefa Senol et Al ed that this number will reach 380 million by 2025 (9). In this study, we aimed to investigate the value of HbA1c levels among patients with PAD and who had not been diagnosed with DM. Materials and methods This prospective study was performed with a total of 224 participants between June 2013 and June The participants were divided into two groups, as follows: Group 1 (PAD group) included 112 patients with PAD (mean age: 57±12 years, 84 males) and no diagnosis of DM, and while Group 2 (control group) included 112 participants (mean age: 54±11 years, 80 males) with normal physical examination results and normal lower extremity arterial duplex ultrasonography (USG) findings when examined for PAD. A complete clinical evaluation, including detailed clinical and family histories, physical examination, and ankle-brachial index measurement was received for all participants. Moreover, their demographic characteristics and cardiovascular risk factors were noted. Those with a systolic blood pressure 140 mmhg or a diastolic blood pressure 90 mmhg, as well as those receiving an antihypertensive therapy, were regarded as hypertensive. Blood samples were obtained for routine hematological and biochemical tests following a 12-hour fasting period. All participants had been diagnosed with lower extremity PAD via at least one noninvasive or invasive method, such as arterial duplex USG, digital subtraction angiography, magnetic resonance angiography, or computerized tomographic angiography. Patients who had a history of type 2 DM and were receiving an antidiabetic therapy (oral hypoglycemic agents or insulin) were regarded as diabetics, and they were excluded from the study in both groups. In addition to diabetics, individuals with renal or hepatic failure, endocrine disorders; low (< 10 g/dl) hemoglobin levels, or hemoglobinopathy; patients who were receiving cardiovascular drugs due to a cardiac disease; those with any known systemic disorders; pregnant patients; and individuals who had undergone surgery in previous 3 months were excluded from the study. PAD is diagnosed based on medical and family histories, a physical examination that includes ankle-brachial index measurement, and diagnostic test results. The most commonly used diagnostic tests for PAD in our clinical practice are duplex USG and DSA. Duplex USG is a noninvasive method that visualizes the arteries with sound waves and measures the blood flow in an artery to indicate the presence of a blockage. Angiography provides a roadmap of the arteries. During an angiogram, a contrast agent is injected into the artery and X-rays are taken to visualize blood flow, examine the arteries in the legs, and pinpoint any blockages that may be present. In this study, two groups were compared according to their clinical and demographic characteristics, as well as the levels of some biochemical parameters, including fasting blood glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, urea, creatinine, and particularly HbA1c levels. Thus, the importance of HbA1c levels in patients with PAD was investigated. All participants were informed about the purposes of the study, and their informed consents were obtained. Moreover, the local ethics committee approved the study protocol. Plasma Glucose and HbA1c measurement technique The ADAMS A1c HA-8160 device was utilized for HbA1c measurement. HbA1c levels were measured, and the reference range was determined to be μmol/l. Furthermore, plasma glucose levels were measured using the AU 5800 equipment. The normal plasma glucose reference range was determined as mg/dl ( mmol/l). Prospective studies have shown that 12-25% of the cases with HbA1c levels between 5.5 and 6% develop DM in five years (10-12), and therefore these values are important. Thus, we used the same reference range in our study. Statistical analysis The statistical analyses were performed using Statistical Package for Social Sciences (SPSS) 11.5 package program (SPSS Inc, Chicago, IL, USA). Chi-square test was used for the categorical variables; in addition, intergroup comparisons were carried out using the one-way analysis of variance (ANOVA) test. Intragroup comparisons of the parameters were performed using t-test and Mann- Whitney U test. The results were analyzed with a confidence interval of 95%, and p<0.05 was regarded as statistically significant.

3 Is Hemoglobin A1c a valuable parameter in non-diabetic patients with peripheral arterial disease? 913 Results The demographic and baseline clinical characteristics of participants, and the comparison of HbA1c levels between the groups are presented in Tables 1 and 2. PAD group Control group N % Mean±SD N % Mean.±SD The proportions of hypertension, smoking, and family history of DM, as well as the fasting blood glucose levels, were significantly higher in PAD group when compared with control group (p< 0.05). Two groups were statistically similar in terms of age, gender, proportions of hyperlipidemia, and levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, urea and creatinine (p>0.05). The average HbA1c level was 5.8±1.3 μmol/l in PAD group, while it was 5.1±0.4 mol/l in control group; and this difference was statistically significant (p= 0.001). P value Age (years) 57±14 54± Gender Male Female Risk factors Hypertension Hyperlipidemia Smoking Laboratory values Fasting blood glucose (mg/dl) ± ± Total cholesterol (mg/dl) ± ± LDL cholesterol (mg/dl) ± ± HDL cholesterol (mg/dl) 41.4 ± ± Triglyceride (mg/dl) 154.8± ± Urea (mg/dl) 35.3 ± ± Creatinine (mg/dl) 0.84 ± ± Family history of DM Table 1: The demographic and baseline clinical characteristics of the groups. DM: Diabetes mellitus; HDL: High density lipoprotein; LDL: Low density lipoprotein; PAD: Peripheral arterial disease; SD: Standard deviation. PAD group Control group P value HbA1c (µmol/l) 5.8 ± ± N (%) N (%) < (30.3) 42 (75) (44.6) 11(19.6) > (25) 3(5.3) Table 2: Comparison of HbA1c levels between the groups. HbA1c: Hemoglobin A1c; PAD: Peripheral arterial disease Discussion PAD is a manifestation of systemic atherosclerosis, which signifies an increased risk of cardiovascular diseases. However, it has received less attention than other atherosclerotic disorders due to underdiagnosis and undertreatment (13). It has been estimated that more than 30 million people are affected by PAD worldwide; moreover, it has been reported that the prevalence rates of this disease are 17% in females and 20% in males older than 65 years (14). In contrast, DM is one of the most common and important public health crises, and nowadays, 8.3% of adults worldwide are estimated to have diabetes. DM is a serious, fatal condition, and it represents a major risk factor for cardiovascular diseases. Patients with DM have a 2-4 times higher risk of cardiovascular disease-associated mortality than those without DM. However, only half of patients with type 2 diabetes-the most common type of DM-are aware of their conditions (15,16). High levels of HbA1c in patients without DM are also claimed to be predictive of cardiovascular morbidity and mortality (17). In several studies, slowly progressive cardiovascular disease in diabetic patients was shown to be preventable with proper glycemic and metabolic control (18,19). Some prospective studies have reported an incidence of 5-year DM development of 12-25% in patients with HbA1c levels of μmol/l (10-12). In our study, we analyzed that HbA1c levels in three ranges, namely <5.5, and >6.0 μmol/l. In PAD group, there were 50 patients (44.6%) with HbA1c levels of μmol/l and 28 patients (25%) with HbA1c levels >6.0 μmol/l.

4 914 Mehmet Ugur Es, Sefa Senol et Al In 70% of the nondiabetic PAD patients, HbA1c levels were in the range of DM or represented a high risk of DM development. We consulted with these patients at our hospital s Endocrinology Clinic. Diagnosis of DM was established in eight (14.2%) of the patients, and routine follow-up was scheduled for all of the others for potential diagnosis of DM in future. Large epidemiological studies have demonstrated that HbA1c is associated with complications even in case of nondiabetic glucose levels, similar to cardiovascular diseases (20,21). The landmark studies of diabetes, which are the Diabetes Control and Complications Trial (DCCT) and the 'United Kingdom Prospective Diabetes Study ' (UKPDS) have shown that regulation of blood glucose levels can delay the occurrence and progression of microvascular complications (22,23). Furthermore, the ADVANCE Study has shown that a 0.61% decrease in HbA1c level results in a 24% decrease in mortality due to cardiovascular diseases (24). Besides, only half of patients with type 2 DM are aware of their condition. It is interesting to note that in 70% of all cases, HbA1c levels were within the range in which DM can be observed. Several risk factors that play a role in the development of PAD have been defined in the literature. Specifically, advanced age, smoking, DM, hypertension, and hyperlipidemia are the most cited PAD risk factors (25,26). In our study, the incidence of hypertension, smoking, family history of DM, and fasting blood glucose levels were significantly higher in the PAD group; these are similar to the risk factors identified in the literature. However, the cholesterol (total, LDL, and HDL cholesterol) and triglyceride levels were not significantly higher in patients with PAD. Therefore, an interesting point is that hyperlipidemia could not be accepted as a risk factor in our study. One of the limitations of this study was our relatively small number of study population. A larger sample could have increased the statistical power of our study. In conclusion, we consider that the routine screening of HbA1c in patients with PAD would be useful for the early diagnosis of prediabetes and DM, as well as for the prevention of the potential complications of DM that could arise in future. References 1) Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA; TASC II Working Group, et al. Inter- Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007; 33(Suppl 1): ) Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013; 382: ) Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002; 287: ) Rhee SY, Kim YS. Peripheral arterial disease in patients with type 2 diabetes mellitus. Diabetes Metab J 2015; 39: ) Wang W, Lee ET, Fabsitz R, Welty TK, Howard BV. Using HbA(1c) to improve efficacy of the american diabetes association fasting plasma glucose criterion in screening for new type 2 diabetes in American Indians: the strong heart study. Diabetes Care 2002; 25: ) American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012; 35(Suppl 1): ) Rohlfing CL, Little RR, Wiedmeyer HM, England JD, Madsen R, et al. Use of GHb (HbA1c) in screening for undiagnosed diabetes in the U.S. population. Diabetes Care 2000; 23: ) Diabetes Atlas. 4th ed. Brussels: International Diabetes Federation; ) Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and Diabetes Res Clin Pract 2011; 94: ) Pradhan AD, Rifai N, Buring JE, Ridker PM. Hemoglobin A1c predicts diabetes but not cardiovascular disease in nondiabetic women. Am J Med 2007; 120: ) Sato KK, Hayashi T, Harita N, Yoneda T, Nakamura Y, et al. Combined measurement of fasting plasma glucose and A1C is effective for the prediction of type 2 diabetes: the Kansai Healthcare Study. Diabetes Care 2009; 32: ) Geiss LS, Pan L, Cadwell B, Gregg EW, Benjamin SM, Engelgau MM. Changes in incidence of diabetes in U.S. adults, Am J Prev Med 2006; 30: ) Haigh K, Bingley J, Golledge J, Walker PJ. Peripheral arterial disease - screening in general practice. Aust Fam Physician 2013; 42: ) Welten GM, Schouten O, Chonchol M, Hoeks SE, Bax JJ, et al. Prognosis of patients with peripheral arterial disease. J Cardiovasc Surg (Torino) 2009; 50: ) Paul SK, Klein K, Thorsted BL, Wolden ML, Khunti K. Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes. Cardiovasc Diabetol 2015; 14: 100.

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