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INTRODUCTION
As a major risk factor for cardiovascular disease (CVD) and all-cause mortality, hypertension has become a global health challenge [1]. The latest national survey from China has shown that the prevalence of hypertension is approximately 45% in adults aged 35–75 years [2]. Diabetes is a well-recognized contributing factor for hypertension [3], and its presence can complicate hypertension management [4, 5]. This is partly reflected by data demonstrating that individuals with both hypertension and diabetes exhibit a markedly increased risk of CVD or all-cause mortality than those with only hypertension [6, 7]. Previous studies have shown that hypertension is associated with a higher risk of diabetes compared with normal blood pressure [8, 9]. Therefore, early detection of diabetes among hypertensive individuals is of clinical importance, as it would enable the implementation of efficient interventions in a timely manner. However, to date, no study has focused on detecting diabetes in this population.
Hemoglobin A1c (HbA1c) reflects the average blood glucose level in the preceding 8–12 weeks and can be measured without fasting; the American Diabetes Association (ADA) recommended using HbA1c to detect diabetes or individuals at risk for diabetes in 2010, after years of debate [10]. Several studies have investigated the performance of HbA1c in detecting undiagnosed diabetes across a spectrum of diverse populations such as general adults [11, 12], gestational women [13], and children [14]. However, its performance among hypertensive individuals and how to better facilitate its use in this population (e.g., how to rule out diabetes) remain largely unknown. Current ADA guidelines recommend an HbA1c cut-off point of 6.5% (48 mmol/mol) for diagnosing diabetes [10]; however, it is unclear whether this cut-off point is suitable for hypertensive individuals.
Therefore, we aimed to evaluate the performance of HbA1c in diabetes screening, as well as to identify its optimal cut-off point for community-dwellers with hypertension. We also compared the diagnostic efficacy of the newly derived HbA1c cut-off point with that of the recommended 6.5% (48 mmol/mol) cut-off point [10], as well as the differences in cardiometabolic risk profiles between individuals who were not diagnosed as having diabetes and those who were diagnosed as having diabetes using the newly derived HbA1c cut-off point.
MATERIALS AND METHODS
Study population
All study individuals were from the Study on Evaluation of iNnovated Screening tools and determInation of optimal diagnostic cut-off points for type 2 diaBetes in Chinese muLti-Ethnic (SENSIBLE) study [15] and the SENSIBLE-Addition study (see below). In the present study, which had a prospective cross-sectional design, individuals who were 20–70 years old and diagnosed as having hypertension, but free of known diabetes, were selected [15]. Eligible individuals from the SENSIBLE study were split randomly into two groups: one (70% of the sample) to assess the performance of HbA1c in detecting diabetes (the exploration dataset) and another (the remaining 30%) for internal validation (the internal validation dataset). The SENSIBLE-Addition study (the external validation dataset) was used for external validation. The protocols for the SENSIBLE and SENSIBLE-Addition studies were approved by the Ethical Review Committees of Zhongda Hospital, Southeast University, Nanjing, China and the other 16 participating hospitals/institutes in China. All individuals provided written informed consent prior to participation. This study followed the STARD guidelines [16].
The anthropometric and biochemical characteristics of individuals in the exploration (N=2,868), internal validation (N=1,228), and external validation (N=2,431) datasets are shown in Table 1. Compared with the exploration and internal validation datasets, individuals in the external validation dataset were younger, had higher body mass index (BMI) and waist circumference (WC) values, and showed lower systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-c) levels (all P<0.05). The prevalence of undiagnosed diabetes among these three cohorts were 14.2%, 14.5%, and 17.5%, respectively.
SENSIBLE study
A cross-sectional survey was conducted in seven provinces in China from November 1st, 2016 to June 30th, 2017 [15]. An age- and sex-stratified, random sample of 13,620 community-dwellers who had lived ≥5 years in their current residence was invited, and 12,017 of the invited individuals participated in this study, with 4,096 eligible for analysis (Fig. 1A).
All individuals were asked to complete a questionnaire containing information regarding their sociodemographic characteristics, lifestyle factors, and medical history. Body weight, height, and WC were measured using standard methods, and BMI was calculated. Blood pressure was measured using an electronic sphygmomanometer (YE680E, Jiangsu Yuyue Medical Equipment Inc., Nanjing, Jiangsu, China) [15]. All individuals were asked to fast for at least 10 hours before receiving a 75 g standardized oral glucose tolerance test (OGTT), for which venous blood samples (5 mL EDTA tubes) were drawn before and two hrs post glucose loading. Blood samples were centrifuged at 1,000–1,200×g for 5 minutes at room temperature (around 22–25°C) within 30 minutes of collection and shipped at 4°C by air to Nanjing Adicon Clinical Laboratories, Nanjing, China. Fasting plasma glucose (FPG), 2-hours postprandial glucose (2h-PG), TC, triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), and LDL-c levels were measured using the automated analyzer, Synchron LX-20 (Beckman Coulter Inc., Fullerton, CA, USA). Specifically, the intra-assay and inter-assay coefficients of variation for blood glucose were both ≤3%. HbA1c was determined with a D-10 Hemoglobin Analyzer (Bio-Rad Inc., Hercules, CA, USA) using an HPLC-based method. This method was certified by the National Glycohemoglobin Standardization Program and standardized to the Diabetes Control and Complications Trial assay approach [17]. In this study, the intra-assay coefficient of variation for HbA1c was 0.81–1.67%, and the inter-assay coefficient of variation for HbA1c was 1.35–2.27%.
SENSIBLE-Addition study
This study had a design similar to that of the SENSIBLE study; however, it was conducted in the Jiangsu Province from April 15th, 2017 to July 31st, 2017, together with liver function measurements and acquisition of additional information regarding health care needs. In total, 5,274 individuals completed a questionnaire survey and underwent an OGTT. Of these, 2,431 were eligible for the external validation dataset (Fig. 1B). Laboratory markers, including FPG, 2h-PG, HbA1c, TC, TG, HDL-c, and LDL-c were analyzed using the same approaches as outlined for the SENSIBLE study.
Definitions
Hypertension was defined as SBP ≥140 mmHg or DBP ≥90 mmHg on average, a self-reported history of hypertension, or a self-reported use of antihypertensive drugs [2]. Diabetes was diagnosed based on the 1999 WHO criteria: FPG ≥7.0 mmol/L, 2h-PG ≥11.1 mmol/L, or both [18]. The 10-year risk score of CVD was calculated according to the Framingham Risk Score for predicting CVD [19]. True-positive cases were defined as individuals with confirmed diabetes based on the 1999 WHO criteria who could be identified as having diabetes by HbA1c at the derived cut-off point, while false-negative cases were defined as individuals with confirmed diabetes based on the 1999 WHO criteria who could not be identified as having diabetes by HbA1c at the derived cut-off point. Screen-positive cases were defined as individuals with HbA1c above the derived cut-off point, while screen-negative cases were defined as individuals with HbA1c below the derived cut-off point.
Statistical analysis
Statistical analyses were conducted using STATA version 14.0 (StataCorp LP, College Station, TX, USA). As the continuous variables were non-normally distributed (assessed by Shapiro-Wilk normality test), they are presented as the median (interquartile range). Categorical variables are expressed as a number (proportion). Differences in continuous and categorical variables were determined using the Kruskal-Wallis test (at least three groups) or Wilcoxon rank-sum test (two groups) and the Chi-squared test, respectively. The diagnostic efficacy of HbA1c in detecting diabetes was evaluated using the area under the ROC (AUROC) curve. The optimal HbA1c cut-off point was determined by minimizing the [(1−sensitivity)2+(1−specificity)2] score, which represents the maximum sum of the sensitivity and specificity [20]. Sensitivities, specificities, and AUROCs were compared using the methods proposed by Altman and Bland [21]. Moreover, based on the methods described by Lu, et al. [22], the HbA1c value at the 2.5th percentile was determined as the cut-off point for ruling out diabetes, while that at the 97.5th percentile was determined as the cut-off point for ruling in diabetes. Subgroup analyses of hypertension awareness (known vs unknown), age (<50, 50–60, vs 60–70 years), and exercise status (regular vs irregular) and sensitivity analyses, excluding individuals using statins and those with anemia, were performed to assess the robustness of the primary results. To increase the data analysis statistical power, a meta-analytical approach using a random-effects model, as well as a combination of all three cohorts at the individual patient level, was used. All statistical tests were two-sided, with P<0.05 considered statistically significant.
RESULTS
Performance of HbA1c in detecting diabetes
The performance of HbA1c in detecting diabetes among the exploration population is presented in Table 2. Increasing the HbA1c cut-off point resulted in decreased sensitivity and negative predictive values, but increased specificity and positive predictive values. An HbA1c cut-off point of 5.8% (40 mmol/mol) yielded the best trade-off for sensitivity and specificity, showing a sensitivity of 76.2% and a specificity of 74.5%. Using the derived 5.8% (40 mmol/mol) HbA1c cut-off point for detecting diabetes, the internal validation dataset showed sensitivity and specificity values similar to those of the exploration dataset (both P>0.70; Table 2). However, when the suggested diagnostic HbA1c cut-off point of 6.5% (48 mmol/mol) [10] was applied, the sensitivity was only 44.2% in the exploration dataset and further decreased to 39.9% in the internal validation dataset and 33.1% in the external validation dataset.
The AUROCs of HbA1c in detecting undiagnosed diabetes were 0.842 (95% confidence interval [CI], 0.819–0.865) in the exploration dataset (Fig. 2A), 0.832 (95% CI, 0.794–0.870) in the internal validation dataset (Fig. 2B), and 0.829 (95% CI, 0.806–0.853) in the external validation dataset (Fig. 2C). The AUROCs of both validation datasets were comparable to that of the exploration dataset (P=0.66 and 0.44, respectively). The HbA1c AUROC remained largely unchanged following the exclusion of individuals using statins or with anemia (data not shown).
Subgroup analyses showed that the HbA1c AUROC was comparable among groups stratified by hypertension awareness, age, or exercise status in the exploration and validation datasets (all P>0.05; Table 3). To enhance the statistical power, the AUROCs from all three cohorts were pooled using a random-effects meta-analysis model. The results indicated that there was no significant difference between women and men (0.859 vs. 0.820, P=0.09) and between the other subgroups listed in Table 3 (all P>0.05).
Comparisons between individuals identified as true-positive and false-negative
As all the three cohorts used comparable survey procedures with overall identical information, they were combined to increase the statistical power for further comparisons between individuals identified as true-positive and false-negative using the derived HbA1c cut-off point of 5.8% (40 mmol/mol). The results suggested that individuals who were true-positive for diabetes had a more unfavorable cardiometabolic risk profile than those who were false-negative (Table 4). Moreover, true-positive individuals had a higher 10-year risk score of CVD than false-negative individuals (26.7% vs 24.2%, P=0.01). In addition, screen-positive individuals exhibited a higher 10-year risk score of CVD than screen-negative individuals (Table 4).
Using HbA1c to rule out or rule in diabetes
Among individuals with undiagnosed diabetes (based on the 1999 WHO criteria) in the exploration dataset, the HbA1c value at the 2.5th percentile was approximately 5.0% (31 mmol/mol). Therefore, an HbA1c cut-off point of 5.1% (32 mmol/mol) was chosen to rule out diabetes. For individuals without diabetes, the HbA1c value at the 97.5th percentile was approximately 6.3% (45 mmol/mol) [22]; thus, an HbA1c cut-off point of 6.4% (46 mmol/mol) was selected to rule in diabetes.
When an HbA1c cut-off point of 6.4% (46 mmol/mol) was applied, 79.2% of the diabetes cases from the internal validation dataset and 82.9% of those from the external validation dataset could be ruled in. Using an HbA1c cut-off point of 5.1% (32 mmol/mol), only 4.0% of the diabetes cases in the internal validation dataset and 3.9% of those in the external validation dataset could be ruled out. Moreover, if an HbA1c cut-off point of 6.4% (46 mmol/mol) was selected for ruling in diabetes, approximately 25.4% of the hypertensive individuals with HbA1c ≥5.8% (40 mmol/mol) in the internal validation dataset and 27.9% in the external validation dataset would not require an OGTT for diabetes confirmation.
DISCUSSION
Our study, which comprised three cross-sectional cohorts, suggests that HbA1c at 5.8% (40 mmol/mol) might be the optimal cut-off point for diabetes screening among community-dwellers with hypertension. Individuals who were not diagnosed as having diabetes by HbA1c at 5.8% (false-negative individuals) had a lower 10-year CVD risk score and a more favorable cardiometabolic risk profile than those correctly identified as having diabetes (true-positive individuals). In addition, HbA1c ≤5.1% (32 mmol/mol) and ≥6.4% (46 mmol/mol) may assist in specifying the absence and presence of diabetes, respectively.
The performance of HbA1c in detecting diabetes has received substantial interest [11, 12, 23, 24]. In a systematic review of nine studies, Bennett, et al. [11] suggested that HbA1c at 6.1% (43 mmol/mol) could be employed as the optimal cut-off point for detecting diabetes but argued that population-specific cut-offs may vary by the population prevalence of diabetes. Partly in accordance with their argument, our study showed that an HbA1c cut-off point of 5.8% (40 mmol/mol) provides the best trade-off in screening for diabetes among community-dwellers with hypertension who have a higher prevalence of diabetes than among those without hypertension [2].
The choice of HbA1c at 5.8% (40 mmol/mol) as the optimal cut-off point for detecting diabetes in hypertensive individuals could be partly supported by the recent observation of Li, et al. [23] that high-risk populations with HbA1c values of 5.5% (37 mmol/mol)−6.1% (43 mmol/mol) exhibit an impaired β-cell function and an ameliorated cardiometabolic risk profile. Moreover, this choice corresponds well with the latest data indicating that the optimal cut-off point of HbA1c for detecting diabetes should be lower than that recommended by the ADA (6.5%; 48 mmol/mol), especially in Asian countries [24]. Franco, et al. [25] pointed out that the ADA-proposed HbA1c cut-off point was adequate for detecting diabetes in a high-risk population, presenting a sensitivity of 71.3% and a specificity of 90.5%. This contrasts with our results and those of another study, which showed that an HbA1c cut-off point of 6.5% (48 mmol/mol) would miss identifying a large proportion of diabetes cases (up to two-thirds) [26].
Our study showed that the accuracy of HbA1c in detecting undiagnosed diabetes would not be affected by sex. Moreover, we found that age may also not influence the accuracy of HbA1c in detecting diabetes, which is consistent with some results of Lee, et al. [27]. Furthermore, our study suggests that neither regular exercise, which reduces the risk of diabetes [28], nor medications, such as statins, which increase the risk of diabetes [29], weaken the performance of HbA1c in detecting diabetes.
Although hypertensive individuals with an HbA1c ≥5.8% (40 mmol/mol) exhibited a significantly higher 10-year risk score of CVD than those with an HbA1c <5.8% (40 mmol/mol), approximately 24–32% of the individuals with previously undiagnosed diabetes might be missed by employing the cut-off point of 5.8% for diabetes detection. This might be because these individuals (false-negative cases) showed a more favorable cardiometabolic risk profile and had a lower risk of CVD than true-positive individuals.
Furthermore, our study demonstrates that an HbA1c cut-off point of 5.1% (32 mmol/mol) could be applied to rule out diabetes and that the prevalence of diabetes begins to rise when HbA1c reaches 5.2% (33 mmol/mol)−5.7% (39 mmol/mol) (data not shown). Thus, hypertensive individuals with an HbA1c of 5.2% (33 mmol/mol)−5.7% (39 mmol/mol) may have an increased risk of developing diabetes and, therefore, need a regular check-up for diabetes and apply certain lifestyle interventions to prevent progression to diabetes [28]. Although HbA1c ≥5.8% (40 mmol/mol) showed robust sensitivity in detecting diabetes, this cut-off point could lead to a misdiagnosis rate of up to 25.5%. Thus, subsequent confirmatory testing using OGTT might be necessary for all individuals with an HbA1c ≥5.8% (40 mmol/mol). However, based on our results that HbA1c ≥6.4% (46 mmol/mol) has sufficient capability to indicate the presence of diabetes, it would be practical to advise that only hypertensive individuals with an HbA1c of 5.8% (40 mmol/mol)−6.3% (45 mmol/mol) undergo confirmatory testing.
The strengths of this study include the facts that it enrolled a large and representative sample and used internal and external validation datasets to test the results derived from the exploration population. Moreover, to the best of our knowledge, this is the first study that assessed the performance of HbA1c in community-dwellers with hypertension. However, this study has some limitations. First, diabetes was confirmed only based on a single OGTT. Second, blood pressure was measured only on a single day, while hypertension confirmation requires three blood-pressure measurements on separate days. However, it is somewhat impractical to measure blood pressure in triplicate on different days in a large-scale epidemiological study [30]. Finally, although our sensitivity analysis suggests that the presence of anemia did not significantly influence the performance of HbA1c, other conditions, including hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency, may affect the relationship between HbA1c and diabetes detection [17].
In conclusion, this study suggests that HbA1c has reasonable diagnostic efficacy for detecting diabetes in community-dwellers with hypertension and that HbA1c ≥5.8% (40 mmol/mol) could be employed for screening for diabetes. HbA1c ≤5.1% (32 mmol/mol) and ≥6.4% (46 mmol/mol) may specify the absence and presence of diabetes in this population, respectively. Hypertensive individuals with HbA1c between 5.2% (33 mmol/mol)−5.7% (39 mmol/mol) would benefit from ongoing and regular check-ups for diabetes, while those with HbA1c between 5.8% (40 mmol/mol)−6.3% (45 mmol/mol) may require confirmatory testing.
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