Clinical and Experimental Pharmacology and Physiology (2015) 42, 582–587
doi: 10.1111/1440-1681.12394
ORIGINAL ARTICLE
Associations of glycated haemoglobin A1c and glycated albumin with subclinical atherosclerosis in middle-aged and elderly Chinese population with impaired glucose regulation Xiaojing Ma,1 Yun Shen,1 Xiang Hu, Yaping Hao, Yuqi Luo, Junling Tang, Jian Zhou, Yuqian Bao and Weiping Jia Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai, China
SUMMARY The aim of this study was to investigate the correlations of glycated haemoglobin A1c (HbA1c) and glycated albumin (GA) with subclinical atherosclerosis in middle-aged and elderly Chinese populations with impaired glucose regulation (IGR). In total, 640 subjects with IGR and no history of cardiovascular disease or carotid artery plaque were recruited for this study (256 men, 384 women; age range, 40–70 years). The carotid intima-media thickness (C-IMT) measured by carotid ultrasonography was used as an indicator of subclinical atherosclerosis. Increased C-IMT was defined as ≥ 0.70 mm (upper quartile). HbA1c and GA were measured with high-performance liquid chromatography and enzymatic method, respectively. The average HbA1c and GA among all 640 subjects were 5.7 0.3% and 14.0 1.1%, respectively. HbA1c and GA were higher in subjects with increased CIMT than in subjects with normal C-IMT (5.8 0.3% vs 5.7 0.3% and 14.2 1.0% vs 13.9 1.1%, respectively; both P < 0.01). Correlation analysis showed that both HbA1c and GA were positively correlated with C-IMT (r = 0.135 and 0.112, respectively; both P < 0.01). Logistic regression analysis revealed that both HbA1c (odds ratio (OR), 2.630; 95% confidence interval (95% CI), 1.401–4.935; P = 0.003) and GA OR, 1.215; 95% CI, 1.008–1.466; P = 0.041) were independent risk factors for increased C-IMT. Both HbA1c and GA reflect the risk of subclinical atherosclerosis in middle-aged and elderly Chinese populations with IGR. Key words: carotid intima-media thickness, glycated albumin, glycated haemoglobin A1c, impaired glucose regulation, subclinical atherosclerosis.
Correspondence: Yuqian Bao and Weiping Jia, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China. Emails: [email protected]; [email protected] 1
Contributed equally to this work.
Received 26 November 2014; revision 19 January 2015; accepted 1 February 2015. © 2015 Wiley Publishing Asia Pty Ltd
INTRODUCTION Impaired glucose regulation (IGR) is defined as the intermediate state of glycemic metabolism between normal glucose tolerance (NGT) and diabetes. As reported by the China National Diabetes and Metabolic Disorders Study conducted between the years 2007 and 2008, the prevalence of IGR in China was 15.5%.1 Atherosclerosis is characterized by chronic inflammation, consisting of stages of subclinical atherosclerosis and end-stage lesions. Previous studies have shown that the occurrence and development of atherosclerosis have already started before an established diagnosis of diabetes, when the blood glucose level has not yet reached the diagnostic criteria for diabetes.2,3 Therefore, IGR is an important risk factor for both diabetes and cardiovascular disease (CVD).4 Early detection of subclinical atherosclerosis is of profound significance for the prevention of CVD. The carotid intima-media thickness (C-IMT) measured by carotid ultrasonography is often applied to screening for the presence of subclinical atherosclerosis. Previous research has demonstrated that C-IMT is directly correlated with the risk of coronary disease and functions as an independent risk factor for CVD.5,6 Recently, various clinical studies have shown that in subjects with IGR, C-IMT has increased while its progression can be slowed by treatment with certain drugs.7–9 Glycated haemoglobin A1c (HbA1c) is now the gold standard parameter for evaluation of glycemic control, reflecting an average glycemic level during the previous 2–3 months. Studies have shown that elevated in HbA1c is positively correlated with an increase in C-IMT among not only patients with diabetes and IGR, but also those with NGT; HbA1c thus plays an important role in detecting the occurrence of atherosclerosis or subclinical atherosclerosis.10–12 Glycated albumin (GA), the early-stage glycation product of the nonenzymatic glycation reaction between glucose and serum albumin, reflects the average glycemic level during the previous 2–3 weeks. GA is superior to HbA1c in terms of its ability to assess the excursion of postprandial blood glucose.13 However, few reports have addressed the relationship between GA and C-IMT in subjects with IGR. Hyperglycemia in patients with diabetes is thought to be positively correlated with a risk of CVD. However, the relationships
Glycemic markers and subclinical atherosclerosis between several glycemic markers (e.g., HbA1c and GA) and the risk of CVD remain controversial, especially in those with IGR which are rarely reported. Additionally, the prevalence of atherosclerosis is rather high in middle-aged and elderly populations. Therefore, in this study, we aimed to explore the correlations of HbA1c and GA with subclinical atherosclerosis simultaneously. For this purpose, we determined C-IMT by carotid ultrasonography in middle-aged and elderly Chinese subjects with IGR and no history of CVD or carotid artery plaque.
RESULTS Characteristics of subjects In total, 640 community-based individuals with IGR were included in the present study (256 men, 384 women). The subjects’ mean age was 54.85 6.78 years. Subjects with isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG and IGT constituted 18.28% (n = 117), 69.84% (n = 447), and 11.88% (n = 76), respectively, of the entire study population (Fig. 1). The difference in C-IMT among these three groups was not statistically significant (P = 0.112). The C-IMT in men was significantly higher than that in women (0.63 0.09 mm vs 0.61 0.08 mm, P < 0.01). The participants were divided into two groups: those with normal C-IMT and those with increased C-IMT (Table 1). Subjects with increased C-IMT were older and exhibited greater waist circumference (W), systolic blood pressure (SBP), fasting plasma glucose (FPG), and smoking frequency than those with normal C-IMT (all P < 0.05), while the estimated glomerular filtration rate (eGFR) was lower in those with increased C-IMT (P < 0.05).
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analysis showed that HbA1c and GA were positively correlated with C-IMT (r = 0.135 and 0.112, respectively; both P < 0.01). These correlations still existed after adjustments for gender, age, body mass index (BMI), and smoking status (r = 0.104 and 0.113, respectively; both P < 0.01). Logistic regression analysis of C-IMT Multivariate logistic regression analysis was carried out with increased C-IMT as the dependent variable to further identify which variables were independently correlated with increased C-IMT. Traditional cardiovascular risk factors (including gender, age, BMI, W, SBP, diastolic blood pressure (DBP), FPG, 2 h plasma glucose (2hPG), the homeostasis model assessment-insulin resistance index (HOMA-IR), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), C-reactive protein (CRP), eGFR, albumin-to-creatinine ratio (ACR), smoking status, family history of CVD, anti-hypertensive therapy, and lipid-lowering therapy) and HbA1c were included. The results showed, besides gender and age, HbA1c was independently correlated with increased C-IMT (odds ratio (OR), 2.884; 95% confidence interval (95% CI), 1.543–5.390; P = 0.001). When traditional cardiovascular risk factors and GA were designated as the independent variables, all of age, W, smoking status, and GA (OR, 1.277; 95% CI, 1.053–1.549; P = 0.013) were observed to be independently correlated with increased C-IMT. When HbA1c and GA were simultaneously included in the model, both HbA1c (OR, 2.630; 95% CI, 1.401–4.935; P = 0.003) and GA (OR, 1.215; 95% CI, 1.008–1.466; P = 0.041) were independent risk factors for increased C-IMT (Table 2).
DISCUSSION Correlation analysis for associations of HbA1c and GA with C-IMT For subjects with IGR, HbA1c was 5.7 0.3% and GA was 14.0 1.1%. Subjects with increased C-IMT had higher HbA1c and GA when compared with those with normal C-IMT (5.8 0.3% vs 5.7 0.3% and 14.2 1.0% vs 13.9 1.1%, respectively; both P < 0.01, Fig. 2). Spearman correlation
Fig. 1 Percentages of subjects with different glycemic statuses. Subjects were classified as isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG and IGT. , Isolated IFG; , Isolated IGT; , combined IFG and IGT.
This is the first report about the associations of HbA1c and GA with C-IMT in Chinese middle-aged and elderly populations with IGR. Results showed that subjects with isolated IGT accounted for more than two-thirds of all participants, which was consistent with the rate reported by the China National Diabetes and Metabolic Disorders Study Group between 2007 and 2008 (70.7%).1 We found that C-IMT was positively correlated with HbA1c and GA. In addition to HbA1c, GA was also detected as an independent risk factor for the increased C-IMT. Comparison of these two indices revealed that HbA1c could identify elevations in C-IMT more effectively than GA. Subjects with IGR are prone to bear various risk factors for CVD. The 2007–2008 China National Diabetes and Metabolic Disorders Study Group reported that the prevalence of overweight, obesity, hypertension and dyslipidemia in IGR population were 36.25%, 10.05%, 36.43%, and 69.96%, respectively.14 C-IMT measured by ultrasound examination is useful and essential for assessment of the extent of subclinical atherosclerosis. The American College of Cardiology Foundation/American Heart Association guidelines point out that C-IMT is independently correlated with multiple cardiovascular events, the risk of which might increase by 15% with every 0.10-mm increase in C-IMT.15 Therefore, it is of great significance to investigate the CVD risk-related hyperglycemic markers in subjects with IGR. The relationship between HbA1c, a standard indicator of glycemic control, and atherosclerosis has become a research hotspot.
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584 Table 1 Characteristics of the study participants Variable
All participants (n = 640)
Normal C-IMT (n = 492)
Increased C-IMT (n = 148)
n (men/women) Age (years) BMI (kg/m2) W (cm) SBP (mmHg) DBP (mmHg) FPG (mmol/L) 2hPG (mmol/L) HbA1c (%) GA (%) FINS (mU/L) HOMA-IR TC (mmol/L) TG (mmol/L) HDL-c (mmol/L) LDL-c (mmol/L) CRP (mg/L) eGFR (mL/min per 1.73 m2) ACR (lg/mg) C-IMT (mm) Current smoker, n (%) Anti-hypertensive therapy, n (%) ACEI or ARB, n (%) Lipid-lowing therapy, n (%) Family history of CVD, n (%)
256/384 54.85 6.78 24.78 3.18 84.60 8.88 126.20 14.54 78.46 10.89 5.66 0.61 8.44 1.41 5.7 0.3 14.0 1.1 10.17 5.46 2.59 1.50 5.27 0.96 1.89 1.43 1.38 0.32 3.32 0.88 1.47 1.60 100.91 17.87 6.95 (4.47–12.44) 0.62 0.08 122 (19.06) 135 (21.09) 19 (2.97) 16 (2.50) 236 (36.88)
173/319 54.02 6.71 24.74 3.19 84.04 8.72 125.16 13.73 78.08 10.80 5.63 0.61 8.41 1.37 5.7 0.3 13.9 1.1 10.14 5.42 2.57 1.47 5.30 0.98 1.91 1.49 1.38 0.31 3.31 0.87 1.44 1.59 101.86 17.71 6.93 (4.49–11.76) 0.58 0.05 80 (16.26) 99 (20.12) 13 (2.64) 13 (2.64) 181 (36.79)
83/65** 57.59 6.28** 24.89 3.14 86.46 9.21** 129.65 16.53* 79.72 11.16 5.76 0.61* 8.55 1.55 5.8 0.3** 14.2 1.0** 10.24 5.58 2.65 1.58 5.19 0.88 1.81 1.20 1.36 0.33 3.36 0.89 1.55 1.62 97.75 18.09* 7.32 (4.37–15.15) 0.73 0.05** 42 (28.38)** 36 (24.32) 6 (4.05) 3 (2.03) 55 (37.16)
Data are presented as mean SD, median (interquartile range) or n (%). *P < 0.05, **P < 0.01. C-IMT, carotid intima-media thickness; BMI, body mass index; W, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; 2hPG, 2h plasma glucose; HbA1c, glycated haemoglobin A1c; GA, glycated albumin; FINS, fasting insulin; HOMA-IR, homeostasis model assessment-insulin resistance index; TC, total cholesterol; TG, triglyceride; HDL-c, high-density lipoprotein cholesterol; LDL-c, lowdensity lipoprotein cholesterol; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; ACR, albumin-to-creatinine ratio; ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; CVD, cardiovascular disease.
Previous studies have demonstrated that HbA1c is closely related to C-IMT among individuals at different stages of glucose metabolism. Sander et al.16 investigated 3534 elderly communitydwelling people (882 with diabetes and 2652 without diabetes) in Germany for an average follow-up of 2 years, and found that HbA1c was a predictor of atherosclerosis progression in both diabetic and non-diabetic populations. Additionally, Hung et al.17 found that HbA1c was significantly correlated with subclinical atherosclerosis in 541 Taiwan participants without a history of diabetes (67 of the 541 participants had been newly diagnosed with diabetes). Similarly, in the present study, HbA1c was identified as an independent risk factor for the increased C-IMT, which was also consistent with the results of studies above. Despite the elucidation of the above-described correlations, the associations of HbA1c, FPG, and 2hPG with C-IMT have not been unified yet.10,11,18–20 A community-based study involving 1627 Chinese individuals aged ≥ 40 years with NGT showed that HbA1c was more effective in identifying the risk of CVD than both FPG and 2hPG.11 Di Pino et al.10 evaluated 274 individuals without a history of diabetes (117 of whom had been diagnosed with prediabetes according to HbA1c) and found that HbA1c was superior to both FPG and the post-OGTT test plasma glucose level in identifying the risk of CVD among individuals with prediabetes. Similarly, Bobbert et al.18 evaluated 1219 German participants without diabetes (558 of whom had NGT) and found that HbA1c was a more relevant glycemic marker with respect to
C-IMT, while FPG and 2hPG exhibited no relationship with C-IMT in individuals with NGT. Other studies involving German and Italian participants without known diabetes drew a conclusion that 2hPG was more significantly correlated with C-IMT than was either HbA1c or FPG.19,20 It is assumed that differences in race and the concomitant metabolic status might lead to these inconsistent results. Interest in the relationship between GA, a new glycemic marker, and C-IMT has gradually increased. A series of studies involving Chinese patients with type 2 diabetes undergoing coronary angiography showed that GA was an important predictor of the presence and severity of coronary lesions and that its predictive value was superior to that of HbA1c.21,22 However, few studies have focused on the association of GA with C-IMT. The Kyushu and Okinawa Population Study performed by Furusyo et al.23 evaluated 1575 Japanese individuals and found a positive relationship between GA and C-IMT. In a follow-up study of 218 Korean individuals conducted by Song et al.,24 GA could even predict the progression of C-IMT in patients with type 2 diabetes. In summary, GA may be not only a more accurate marker of glycemic control, but also of great predicative value for atherosclerosis. No studies have yet performed a comparison of the associations of both HbA1c and GA with subclinical atherosclerosis simultaneously within one population at home and one abroad. In the present study, when HbA1c and GA were included either
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Glycemic markers and subclinical atherosclerosis (a)
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(b)
Fig. 2 Glycated haemoglobin A1c (HbA1c) and glycated albumin (GA) in subjects with normal and increased carotid intima-media thickness (C-IMT). Data are presented as mean SD.
Table 2 Multivariate logistic regression analysis showing independent factors associated with increased C-IMT Independent variable Gender (women) Age Smoking status HbA1c GA
b 0.635 0.077 0.317 0.967 0.195
SE
OR
95% CI
P
0.253 0.016 0.148 0.321 0.096
0.530 1.080 1.373 2.630 1.215
0.323–0.870 1.046–1.116 1.027–1.837 1.401–4.935 1.008–1.466
0.012 < 0.001 0.032 0.003 0.041
Variables of the original model included: traditional cardiovascular risk factors (gender, age, BMI, W, SBP, DBP, FPG, 2hPG, HOMA-IR, TC, TG, HDL-c, LDL-c, CRP, eGFR, ACR, smoking status, family history of CVD, anti-hypertensive therapy, lipid-lowering therapy), HbA1c and GA. C-IMT, carotid intima-media thickness; OR, odds ratio; CI, confidence interval; HbA1c, glycated haemoglobin A1c; GA, glycated albumin.
separately or simultaneously in the regression analysis, each was found to be an independent risk factor for the increased C-IMT (OR = 2.630 and 1.215, respectively), while FPG and 2hPG were not. This finding may indicate that markers for long-term glycemic control (e.g., HbA1c) are preferable to those for short-term glycemic control (e.g., GA) with respect to their abilities to reflect the thickening in C-IMT. Despite the fact that the plasma glucose level of subjects with IGR might not reach the level required for a diagnosis of diabetes, the relative elevations in HbA1c and GA were able to imply an increased risk of subclinical atherosclerosis. The present study had some limitations. First, it was a crosssectional study, and the relevant causality could not be explained well. Prospective studies are required to confirm causality. Second, the sample size was somewhat small and only comprised a middle-aged and elderly population aged ≥ 40 years. We plan to enlarge the sample size in the near future to obtain more generalized conclusions. In summary, we found that both HbA1c and GA were informative parameters for identification of a higher risk of subclinical atherosclerosis among community-based Chinese middle-aged and elderly individuals with IGR. A study of larger sample is
necessary to verify the ability of HbA1c and GA for predication of subclinical atherosclerosis.
METHODS Study subjects Participants aged ≥ 40 years with IGR from the Shanghai Obesity Study25 during December 2009 to December 2011 were recruited for the present study. All participants had no history of cardiovascular disease, diabetes, or carotid plaque and provided complete clinical data. The exclusion criteria were established to eliminate influences on HbA1c, GA, and C-IMT measurements, as follows: (i) chronic liver and kidney disease; (ii) liver cirrhosis; (iii) hypoproteinemia; (iv) hyperthyroidism or hypothyroidism; (v) acute infection with indication of elevated CRP levels (> 10 mg/L), increased white blood cell count, or urinary tract infection; (vi) malignant tumors; (vii) anemia; (viii) an HbA1c of ≥ 6.5%; and (ix) currently undergoing replacement therapy with glucocorticoids or thyroid hormones. Finally, 640 subjects with IGR were enrolled in this study. Also a questionnaire regarding past and present illness, medication history, and smoking status was completed by each participant. This study was approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. All enrolled subjects provided written informed consent. Anthropometric measurements The BMI was calculated as weight in kilograms divided by height in metres squared. Blood pressure was measured three times after the subjects had rested for more than 10 min; one operator performed all three measurements at 3-min intervals using a sphygmomanometer, and the mean value of the three measurements was recorded. W was measured with a tape horizontally wrapped around the abdomen at the midpoint of the costal margin and iliac crest on the midaxillary line.
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Laboratory measurements All subjects underwent a 75-g oral glucose tolerance test after a 10-h overnight fast. Biochemical variables were analyzed according to previously described methods,26 including FPG, 2hPG, lipid profile (TG, TC, LDL-c, and HDL-c), fasting insulin (FINS), CRP and serum creatinine. The HOMA-IR value was calculated as follows: HOMA-IR = FPG (mmol/L) 9 FINS (mU/L)/22.5.27 The eGFR was calculated as follows: eGFR = (186 9 (serum creatinine/88.4) 1.154 9 (age) 0.203 9 0.742 (if women)).28 The firstmorning and midstream urine samples were collected to measure the levels of urinary albumin by immunonephelometry on the BN II analyzer (Siemens Healthcare Diagnostics, Marburg, Germany) and of creatinine by the sarcosine oxidase-peroxidase-antiperoxidase method on a Hitachi 7600-120 autoanalyzer (Hitachi, Tokyo, Japan), respectively. The ACR was calculated to reflect urinary albumin excretion. HbA1c was measured by high-performance liquid chromatography (Variant II; Bio-Rad, Hercules, CA, USA), and GA was measured by a liquid enzyme method (Hitachi 7600-120; Tokyo, Japan and Lucica GA-L; Asahi Kasei Pharma Corporation, Tokyo, Japan). The inter- and intra-assay coefficients of variance of HbA1c were < 3.40% and < 2.60%, respectively, and those of GA were < 5.10% and < 3.00%, respectively. The measurement ranges of HbA1c and GA values were 3.5–19.0% and 3.2– 68.1%, respectively. Diagnostic criteria According to the 1999 World Health Organization criteria, diabetes was diagnosed as an FPG of ≥ 7.0 mmol/L and/or a 2hPG of ≥ 11.1 mmol/L, and IGR was diagnosed as an FPG of 6.1 to < 7.0 mmol/L and/or a 2hPG of 7.8 to < 11.1 mmol/L.29 The glycemic status of IGR included: (i) isolated IFG (FPG of 6.1 to < 7.0 mmol/L and 2hPG of < 7.8 mmol/L); (ii) isolated IGT (FPG of < 6.1 mmol/L and 2hPG of 7.8 to < 11.1 mmol/L); (iii) combined IFG and IGT (FPG of 6.1 to < 7.0 mmol/L and 2hPG of 7.8 to < 11.1 mmol/L). Smokers were defined as those who smoked at least once daily during the past 6 months or more.30 Carotid ultrasonography An ultrasonographer blinded to the study results scanned all subjects’ common carotid arteries (proximal, middle, and distal walls) from the carotid bifurcation to the distal continuously, using a high-resolution B-mode scanner (Voluson 730 Expert; GE Healthcare, Waukesha, WI, USA) equipped with a 10-MHz probe. C-IMT was measured at the far wall of the right and left common carotid arteries, approximately 1.0–1.5 cm proximal to the carotid bulb, and was defined as the mean value of the maximal thickness of each carotid artery in both sides.26 Increased CIMT was defined as the upper quartile value of the study population (≥ 0.70 mm).11
Statistical analysis Statistical Package for the Social Sciences software (version 16.0; SPSS Inc, Chicago, IL, USA) was used for all statistical analyses. Continuous variables were expressed as mean stan-
dard deviation (SD) or median (interquartile range). Categorical variables were expressed as percentages. All variables were subjected to a normality test. Intergroup comparisons of normally distributed data were carried out using the independent-samples t test. Intergroup comparisons of skewed data were carried out using the Mann–Whitney U test and Kruskal–Wallis test, respectively. Intergroup comparisons of categorical variables were carried out by the Chi-square test. Spearman analysis and partial correlation analysis were performed to explore the correlations of HbA1c and GA with C-IMT. Multivariate logistic regression analysis was performed to identify the factors that affect C-IMT. All P-values of < 0.05 were considered statistically significant.
ACKNOWLEDGEMENTS This work was funded by 973 Program of China (2013CB530606), Project of National Natural Science Foundation of China (81100563 and 81100590), Shanghai Medical Program for Outstanding Young Talent (XYQ2011013), Key Project of Science and Technology of Shanghai (13XD1403000), and Grant from Shanghai Health and Family Planning Commission (2013ZYJB1001).
DISCLOSURE The authors declare they have no conflict of interest. Yuqian Bao and Weiping Jia designed the study. Yun Shen, Xiang Hu, Yaping Hao, and Yuqi Luo collected data. Junling Tang provided technical support. Xiaojing Ma analyzed data and wrote the draft. Jian Zhou, Yuqian Bao and Weiping Jia revised the paper and contributed to the discussion.
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doi: 10.1111/1440-1681.12394
ORIGINAL ARTICLE
Associations of glycated haemoglobin A1c and glycated albumin with subclinical atherosclerosis in middle-aged and elderly Chinese population with impaired glucose regulation Xiaojing Ma,1 Yun Shen,1 Xiang Hu, Yaping Hao, Yuqi Luo, Junling Tang, Jian Zhou, Yuqian Bao and Weiping Jia Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai, China
SUMMARY The aim of this study was to investigate the correlations of glycated haemoglobin A1c (HbA1c) and glycated albumin (GA) with subclinical atherosclerosis in middle-aged and elderly Chinese populations with impaired glucose regulation (IGR). In total, 640 subjects with IGR and no history of cardiovascular disease or carotid artery plaque were recruited for this study (256 men, 384 women; age range, 40–70 years). The carotid intima-media thickness (C-IMT) measured by carotid ultrasonography was used as an indicator of subclinical atherosclerosis. Increased C-IMT was defined as ≥ 0.70 mm (upper quartile). HbA1c and GA were measured with high-performance liquid chromatography and enzymatic method, respectively. The average HbA1c and GA among all 640 subjects were 5.7 0.3% and 14.0 1.1%, respectively. HbA1c and GA were higher in subjects with increased CIMT than in subjects with normal C-IMT (5.8 0.3% vs 5.7 0.3% and 14.2 1.0% vs 13.9 1.1%, respectively; both P < 0.01). Correlation analysis showed that both HbA1c and GA were positively correlated with C-IMT (r = 0.135 and 0.112, respectively; both P < 0.01). Logistic regression analysis revealed that both HbA1c (odds ratio (OR), 2.630; 95% confidence interval (95% CI), 1.401–4.935; P = 0.003) and GA OR, 1.215; 95% CI, 1.008–1.466; P = 0.041) were independent risk factors for increased C-IMT. Both HbA1c and GA reflect the risk of subclinical atherosclerosis in middle-aged and elderly Chinese populations with IGR. Key words: carotid intima-media thickness, glycated albumin, glycated haemoglobin A1c, impaired glucose regulation, subclinical atherosclerosis.
Correspondence: Yuqian Bao and Weiping Jia, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China. Emails: [email protected]; [email protected] 1
Contributed equally to this work.
Received 26 November 2014; revision 19 January 2015; accepted 1 February 2015. © 2015 Wiley Publishing Asia Pty Ltd
INTRODUCTION Impaired glucose regulation (IGR) is defined as the intermediate state of glycemic metabolism between normal glucose tolerance (NGT) and diabetes. As reported by the China National Diabetes and Metabolic Disorders Study conducted between the years 2007 and 2008, the prevalence of IGR in China was 15.5%.1 Atherosclerosis is characterized by chronic inflammation, consisting of stages of subclinical atherosclerosis and end-stage lesions. Previous studies have shown that the occurrence and development of atherosclerosis have already started before an established diagnosis of diabetes, when the blood glucose level has not yet reached the diagnostic criteria for diabetes.2,3 Therefore, IGR is an important risk factor for both diabetes and cardiovascular disease (CVD).4 Early detection of subclinical atherosclerosis is of profound significance for the prevention of CVD. The carotid intima-media thickness (C-IMT) measured by carotid ultrasonography is often applied to screening for the presence of subclinical atherosclerosis. Previous research has demonstrated that C-IMT is directly correlated with the risk of coronary disease and functions as an independent risk factor for CVD.5,6 Recently, various clinical studies have shown that in subjects with IGR, C-IMT has increased while its progression can be slowed by treatment with certain drugs.7–9 Glycated haemoglobin A1c (HbA1c) is now the gold standard parameter for evaluation of glycemic control, reflecting an average glycemic level during the previous 2–3 months. Studies have shown that elevated in HbA1c is positively correlated with an increase in C-IMT among not only patients with diabetes and IGR, but also those with NGT; HbA1c thus plays an important role in detecting the occurrence of atherosclerosis or subclinical atherosclerosis.10–12 Glycated albumin (GA), the early-stage glycation product of the nonenzymatic glycation reaction between glucose and serum albumin, reflects the average glycemic level during the previous 2–3 weeks. GA is superior to HbA1c in terms of its ability to assess the excursion of postprandial blood glucose.13 However, few reports have addressed the relationship between GA and C-IMT in subjects with IGR. Hyperglycemia in patients with diabetes is thought to be positively correlated with a risk of CVD. However, the relationships
Glycemic markers and subclinical atherosclerosis between several glycemic markers (e.g., HbA1c and GA) and the risk of CVD remain controversial, especially in those with IGR which are rarely reported. Additionally, the prevalence of atherosclerosis is rather high in middle-aged and elderly populations. Therefore, in this study, we aimed to explore the correlations of HbA1c and GA with subclinical atherosclerosis simultaneously. For this purpose, we determined C-IMT by carotid ultrasonography in middle-aged and elderly Chinese subjects with IGR and no history of CVD or carotid artery plaque.
RESULTS Characteristics of subjects In total, 640 community-based individuals with IGR were included in the present study (256 men, 384 women). The subjects’ mean age was 54.85 6.78 years. Subjects with isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG and IGT constituted 18.28% (n = 117), 69.84% (n = 447), and 11.88% (n = 76), respectively, of the entire study population (Fig. 1). The difference in C-IMT among these three groups was not statistically significant (P = 0.112). The C-IMT in men was significantly higher than that in women (0.63 0.09 mm vs 0.61 0.08 mm, P < 0.01). The participants were divided into two groups: those with normal C-IMT and those with increased C-IMT (Table 1). Subjects with increased C-IMT were older and exhibited greater waist circumference (W), systolic blood pressure (SBP), fasting plasma glucose (FPG), and smoking frequency than those with normal C-IMT (all P < 0.05), while the estimated glomerular filtration rate (eGFR) was lower in those with increased C-IMT (P < 0.05).
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analysis showed that HbA1c and GA were positively correlated with C-IMT (r = 0.135 and 0.112, respectively; both P < 0.01). These correlations still existed after adjustments for gender, age, body mass index (BMI), and smoking status (r = 0.104 and 0.113, respectively; both P < 0.01). Logistic regression analysis of C-IMT Multivariate logistic regression analysis was carried out with increased C-IMT as the dependent variable to further identify which variables were independently correlated with increased C-IMT. Traditional cardiovascular risk factors (including gender, age, BMI, W, SBP, diastolic blood pressure (DBP), FPG, 2 h plasma glucose (2hPG), the homeostasis model assessment-insulin resistance index (HOMA-IR), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), C-reactive protein (CRP), eGFR, albumin-to-creatinine ratio (ACR), smoking status, family history of CVD, anti-hypertensive therapy, and lipid-lowering therapy) and HbA1c were included. The results showed, besides gender and age, HbA1c was independently correlated with increased C-IMT (odds ratio (OR), 2.884; 95% confidence interval (95% CI), 1.543–5.390; P = 0.001). When traditional cardiovascular risk factors and GA were designated as the independent variables, all of age, W, smoking status, and GA (OR, 1.277; 95% CI, 1.053–1.549; P = 0.013) were observed to be independently correlated with increased C-IMT. When HbA1c and GA were simultaneously included in the model, both HbA1c (OR, 2.630; 95% CI, 1.401–4.935; P = 0.003) and GA (OR, 1.215; 95% CI, 1.008–1.466; P = 0.041) were independent risk factors for increased C-IMT (Table 2).
DISCUSSION Correlation analysis for associations of HbA1c and GA with C-IMT For subjects with IGR, HbA1c was 5.7 0.3% and GA was 14.0 1.1%. Subjects with increased C-IMT had higher HbA1c and GA when compared with those with normal C-IMT (5.8 0.3% vs 5.7 0.3% and 14.2 1.0% vs 13.9 1.1%, respectively; both P < 0.01, Fig. 2). Spearman correlation
Fig. 1 Percentages of subjects with different glycemic statuses. Subjects were classified as isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG and IGT. , Isolated IFG; , Isolated IGT; , combined IFG and IGT.
This is the first report about the associations of HbA1c and GA with C-IMT in Chinese middle-aged and elderly populations with IGR. Results showed that subjects with isolated IGT accounted for more than two-thirds of all participants, which was consistent with the rate reported by the China National Diabetes and Metabolic Disorders Study Group between 2007 and 2008 (70.7%).1 We found that C-IMT was positively correlated with HbA1c and GA. In addition to HbA1c, GA was also detected as an independent risk factor for the increased C-IMT. Comparison of these two indices revealed that HbA1c could identify elevations in C-IMT more effectively than GA. Subjects with IGR are prone to bear various risk factors for CVD. The 2007–2008 China National Diabetes and Metabolic Disorders Study Group reported that the prevalence of overweight, obesity, hypertension and dyslipidemia in IGR population were 36.25%, 10.05%, 36.43%, and 69.96%, respectively.14 C-IMT measured by ultrasound examination is useful and essential for assessment of the extent of subclinical atherosclerosis. The American College of Cardiology Foundation/American Heart Association guidelines point out that C-IMT is independently correlated with multiple cardiovascular events, the risk of which might increase by 15% with every 0.10-mm increase in C-IMT.15 Therefore, it is of great significance to investigate the CVD risk-related hyperglycemic markers in subjects with IGR. The relationship between HbA1c, a standard indicator of glycemic control, and atherosclerosis has become a research hotspot.
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584 Table 1 Characteristics of the study participants Variable
All participants (n = 640)
Normal C-IMT (n = 492)
Increased C-IMT (n = 148)
n (men/women) Age (years) BMI (kg/m2) W (cm) SBP (mmHg) DBP (mmHg) FPG (mmol/L) 2hPG (mmol/L) HbA1c (%) GA (%) FINS (mU/L) HOMA-IR TC (mmol/L) TG (mmol/L) HDL-c (mmol/L) LDL-c (mmol/L) CRP (mg/L) eGFR (mL/min per 1.73 m2) ACR (lg/mg) C-IMT (mm) Current smoker, n (%) Anti-hypertensive therapy, n (%) ACEI or ARB, n (%) Lipid-lowing therapy, n (%) Family history of CVD, n (%)
256/384 54.85 6.78 24.78 3.18 84.60 8.88 126.20 14.54 78.46 10.89 5.66 0.61 8.44 1.41 5.7 0.3 14.0 1.1 10.17 5.46 2.59 1.50 5.27 0.96 1.89 1.43 1.38 0.32 3.32 0.88 1.47 1.60 100.91 17.87 6.95 (4.47–12.44) 0.62 0.08 122 (19.06) 135 (21.09) 19 (2.97) 16 (2.50) 236 (36.88)
173/319 54.02 6.71 24.74 3.19 84.04 8.72 125.16 13.73 78.08 10.80 5.63 0.61 8.41 1.37 5.7 0.3 13.9 1.1 10.14 5.42 2.57 1.47 5.30 0.98 1.91 1.49 1.38 0.31 3.31 0.87 1.44 1.59 101.86 17.71 6.93 (4.49–11.76) 0.58 0.05 80 (16.26) 99 (20.12) 13 (2.64) 13 (2.64) 181 (36.79)
83/65** 57.59 6.28** 24.89 3.14 86.46 9.21** 129.65 16.53* 79.72 11.16 5.76 0.61* 8.55 1.55 5.8 0.3** 14.2 1.0** 10.24 5.58 2.65 1.58 5.19 0.88 1.81 1.20 1.36 0.33 3.36 0.89 1.55 1.62 97.75 18.09* 7.32 (4.37–15.15) 0.73 0.05** 42 (28.38)** 36 (24.32) 6 (4.05) 3 (2.03) 55 (37.16)
Data are presented as mean SD, median (interquartile range) or n (%). *P < 0.05, **P < 0.01. C-IMT, carotid intima-media thickness; BMI, body mass index; W, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; 2hPG, 2h plasma glucose; HbA1c, glycated haemoglobin A1c; GA, glycated albumin; FINS, fasting insulin; HOMA-IR, homeostasis model assessment-insulin resistance index; TC, total cholesterol; TG, triglyceride; HDL-c, high-density lipoprotein cholesterol; LDL-c, lowdensity lipoprotein cholesterol; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; ACR, albumin-to-creatinine ratio; ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; CVD, cardiovascular disease.
Previous studies have demonstrated that HbA1c is closely related to C-IMT among individuals at different stages of glucose metabolism. Sander et al.16 investigated 3534 elderly communitydwelling people (882 with diabetes and 2652 without diabetes) in Germany for an average follow-up of 2 years, and found that HbA1c was a predictor of atherosclerosis progression in both diabetic and non-diabetic populations. Additionally, Hung et al.17 found that HbA1c was significantly correlated with subclinical atherosclerosis in 541 Taiwan participants without a history of diabetes (67 of the 541 participants had been newly diagnosed with diabetes). Similarly, in the present study, HbA1c was identified as an independent risk factor for the increased C-IMT, which was also consistent with the results of studies above. Despite the elucidation of the above-described correlations, the associations of HbA1c, FPG, and 2hPG with C-IMT have not been unified yet.10,11,18–20 A community-based study involving 1627 Chinese individuals aged ≥ 40 years with NGT showed that HbA1c was more effective in identifying the risk of CVD than both FPG and 2hPG.11 Di Pino et al.10 evaluated 274 individuals without a history of diabetes (117 of whom had been diagnosed with prediabetes according to HbA1c) and found that HbA1c was superior to both FPG and the post-OGTT test plasma glucose level in identifying the risk of CVD among individuals with prediabetes. Similarly, Bobbert et al.18 evaluated 1219 German participants without diabetes (558 of whom had NGT) and found that HbA1c was a more relevant glycemic marker with respect to
C-IMT, while FPG and 2hPG exhibited no relationship with C-IMT in individuals with NGT. Other studies involving German and Italian participants without known diabetes drew a conclusion that 2hPG was more significantly correlated with C-IMT than was either HbA1c or FPG.19,20 It is assumed that differences in race and the concomitant metabolic status might lead to these inconsistent results. Interest in the relationship between GA, a new glycemic marker, and C-IMT has gradually increased. A series of studies involving Chinese patients with type 2 diabetes undergoing coronary angiography showed that GA was an important predictor of the presence and severity of coronary lesions and that its predictive value was superior to that of HbA1c.21,22 However, few studies have focused on the association of GA with C-IMT. The Kyushu and Okinawa Population Study performed by Furusyo et al.23 evaluated 1575 Japanese individuals and found a positive relationship between GA and C-IMT. In a follow-up study of 218 Korean individuals conducted by Song et al.,24 GA could even predict the progression of C-IMT in patients with type 2 diabetes. In summary, GA may be not only a more accurate marker of glycemic control, but also of great predicative value for atherosclerosis. No studies have yet performed a comparison of the associations of both HbA1c and GA with subclinical atherosclerosis simultaneously within one population at home and one abroad. In the present study, when HbA1c and GA were included either
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Glycemic markers and subclinical atherosclerosis (a)
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(b)
Fig. 2 Glycated haemoglobin A1c (HbA1c) and glycated albumin (GA) in subjects with normal and increased carotid intima-media thickness (C-IMT). Data are presented as mean SD.
Table 2 Multivariate logistic regression analysis showing independent factors associated with increased C-IMT Independent variable Gender (women) Age Smoking status HbA1c GA
b 0.635 0.077 0.317 0.967 0.195
SE
OR
95% CI
P
0.253 0.016 0.148 0.321 0.096
0.530 1.080 1.373 2.630 1.215
0.323–0.870 1.046–1.116 1.027–1.837 1.401–4.935 1.008–1.466
0.012 < 0.001 0.032 0.003 0.041
Variables of the original model included: traditional cardiovascular risk factors (gender, age, BMI, W, SBP, DBP, FPG, 2hPG, HOMA-IR, TC, TG, HDL-c, LDL-c, CRP, eGFR, ACR, smoking status, family history of CVD, anti-hypertensive therapy, lipid-lowering therapy), HbA1c and GA. C-IMT, carotid intima-media thickness; OR, odds ratio; CI, confidence interval; HbA1c, glycated haemoglobin A1c; GA, glycated albumin.
separately or simultaneously in the regression analysis, each was found to be an independent risk factor for the increased C-IMT (OR = 2.630 and 1.215, respectively), while FPG and 2hPG were not. This finding may indicate that markers for long-term glycemic control (e.g., HbA1c) are preferable to those for short-term glycemic control (e.g., GA) with respect to their abilities to reflect the thickening in C-IMT. Despite the fact that the plasma glucose level of subjects with IGR might not reach the level required for a diagnosis of diabetes, the relative elevations in HbA1c and GA were able to imply an increased risk of subclinical atherosclerosis. The present study had some limitations. First, it was a crosssectional study, and the relevant causality could not be explained well. Prospective studies are required to confirm causality. Second, the sample size was somewhat small and only comprised a middle-aged and elderly population aged ≥ 40 years. We plan to enlarge the sample size in the near future to obtain more generalized conclusions. In summary, we found that both HbA1c and GA were informative parameters for identification of a higher risk of subclinical atherosclerosis among community-based Chinese middle-aged and elderly individuals with IGR. A study of larger sample is
necessary to verify the ability of HbA1c and GA for predication of subclinical atherosclerosis.
METHODS Study subjects Participants aged ≥ 40 years with IGR from the Shanghai Obesity Study25 during December 2009 to December 2011 were recruited for the present study. All participants had no history of cardiovascular disease, diabetes, or carotid plaque and provided complete clinical data. The exclusion criteria were established to eliminate influences on HbA1c, GA, and C-IMT measurements, as follows: (i) chronic liver and kidney disease; (ii) liver cirrhosis; (iii) hypoproteinemia; (iv) hyperthyroidism or hypothyroidism; (v) acute infection with indication of elevated CRP levels (> 10 mg/L), increased white blood cell count, or urinary tract infection; (vi) malignant tumors; (vii) anemia; (viii) an HbA1c of ≥ 6.5%; and (ix) currently undergoing replacement therapy with glucocorticoids or thyroid hormones. Finally, 640 subjects with IGR were enrolled in this study. Also a questionnaire regarding past and present illness, medication history, and smoking status was completed by each participant. This study was approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. All enrolled subjects provided written informed consent. Anthropometric measurements The BMI was calculated as weight in kilograms divided by height in metres squared. Blood pressure was measured three times after the subjects had rested for more than 10 min; one operator performed all three measurements at 3-min intervals using a sphygmomanometer, and the mean value of the three measurements was recorded. W was measured with a tape horizontally wrapped around the abdomen at the midpoint of the costal margin and iliac crest on the midaxillary line.
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Laboratory measurements All subjects underwent a 75-g oral glucose tolerance test after a 10-h overnight fast. Biochemical variables were analyzed according to previously described methods,26 including FPG, 2hPG, lipid profile (TG, TC, LDL-c, and HDL-c), fasting insulin (FINS), CRP and serum creatinine. The HOMA-IR value was calculated as follows: HOMA-IR = FPG (mmol/L) 9 FINS (mU/L)/22.5.27 The eGFR was calculated as follows: eGFR = (186 9 (serum creatinine/88.4) 1.154 9 (age) 0.203 9 0.742 (if women)).28 The firstmorning and midstream urine samples were collected to measure the levels of urinary albumin by immunonephelometry on the BN II analyzer (Siemens Healthcare Diagnostics, Marburg, Germany) and of creatinine by the sarcosine oxidase-peroxidase-antiperoxidase method on a Hitachi 7600-120 autoanalyzer (Hitachi, Tokyo, Japan), respectively. The ACR was calculated to reflect urinary albumin excretion. HbA1c was measured by high-performance liquid chromatography (Variant II; Bio-Rad, Hercules, CA, USA), and GA was measured by a liquid enzyme method (Hitachi 7600-120; Tokyo, Japan and Lucica GA-L; Asahi Kasei Pharma Corporation, Tokyo, Japan). The inter- and intra-assay coefficients of variance of HbA1c were < 3.40% and < 2.60%, respectively, and those of GA were < 5.10% and < 3.00%, respectively. The measurement ranges of HbA1c and GA values were 3.5–19.0% and 3.2– 68.1%, respectively. Diagnostic criteria According to the 1999 World Health Organization criteria, diabetes was diagnosed as an FPG of ≥ 7.0 mmol/L and/or a 2hPG of ≥ 11.1 mmol/L, and IGR was diagnosed as an FPG of 6.1 to < 7.0 mmol/L and/or a 2hPG of 7.8 to < 11.1 mmol/L.29 The glycemic status of IGR included: (i) isolated IFG (FPG of 6.1 to < 7.0 mmol/L and 2hPG of < 7.8 mmol/L); (ii) isolated IGT (FPG of < 6.1 mmol/L and 2hPG of 7.8 to < 11.1 mmol/L); (iii) combined IFG and IGT (FPG of 6.1 to < 7.0 mmol/L and 2hPG of 7.8 to < 11.1 mmol/L). Smokers were defined as those who smoked at least once daily during the past 6 months or more.30 Carotid ultrasonography An ultrasonographer blinded to the study results scanned all subjects’ common carotid arteries (proximal, middle, and distal walls) from the carotid bifurcation to the distal continuously, using a high-resolution B-mode scanner (Voluson 730 Expert; GE Healthcare, Waukesha, WI, USA) equipped with a 10-MHz probe. C-IMT was measured at the far wall of the right and left common carotid arteries, approximately 1.0–1.5 cm proximal to the carotid bulb, and was defined as the mean value of the maximal thickness of each carotid artery in both sides.26 Increased CIMT was defined as the upper quartile value of the study population (≥ 0.70 mm).11
Statistical analysis Statistical Package for the Social Sciences software (version 16.0; SPSS Inc, Chicago, IL, USA) was used for all statistical analyses. Continuous variables were expressed as mean stan-
dard deviation (SD) or median (interquartile range). Categorical variables were expressed as percentages. All variables were subjected to a normality test. Intergroup comparisons of normally distributed data were carried out using the independent-samples t test. Intergroup comparisons of skewed data were carried out using the Mann–Whitney U test and Kruskal–Wallis test, respectively. Intergroup comparisons of categorical variables were carried out by the Chi-square test. Spearman analysis and partial correlation analysis were performed to explore the correlations of HbA1c and GA with C-IMT. Multivariate logistic regression analysis was performed to identify the factors that affect C-IMT. All P-values of < 0.05 were considered statistically significant.
ACKNOWLEDGEMENTS This work was funded by 973 Program of China (2013CB530606), Project of National Natural Science Foundation of China (81100563 and 81100590), Shanghai Medical Program for Outstanding Young Talent (XYQ2011013), Key Project of Science and Technology of Shanghai (13XD1403000), and Grant from Shanghai Health and Family Planning Commission (2013ZYJB1001).
DISCLOSURE The authors declare they have no conflict of interest. Yuqian Bao and Weiping Jia designed the study. Yun Shen, Xiang Hu, Yaping Hao, and Yuqi Luo collected data. Junling Tang provided technical support. Xiaojing Ma analyzed data and wrote the draft. Jian Zhou, Yuqian Bao and Weiping Jia revised the paper and contributed to the discussion.
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