This population-based survey demonstrated that higher HbA1c levels dramatically aggravate the risk of hypertension in subjects without diabetes, further emphasizing the role of abnormal glucose metabolism in the pathogenesis of hypertension. Owing to specific merits, HbA1c generally serves as an effective indicator in the management of diabetes over FPG or postload plasma glucose. First, HbA1c has less biological variability and higher stability and, second, HbA1c could be less affected by relevant factors, such as acute infection, short-term lifestyle alterations, and recent eating behaviors [25]. Third, FPG only reflects the immediate glycemia level at the time of a single measurement; in contrast, HbA1c can stably indicate chronic glycemia levels, which reflect variations in average glycemia level across nearly two to three months. A cohort study consisting of 31,148 adults revealed that HbA1c was closely correlated with all-cause mortality and coronary heart disease in contrast to the fasting glucose [26]. Arbel et al. [27] investigated the relationship between glucometabolic markers (including admission glucose, FPG, and HbA1c) and the severity of coronary artery disease in nondiabetic patients, which indicated that only HbA1c was associated with the severity of coronary artery disease.
The relationship between glycemic control and hypertension can be explained by several possible mechanisms. First, function deficits of pancreatic beta cells, as well as insulin resistance could be indicated by the expression, of HbA1c [9,10]. It was well- recognized that insulin resistance was the common pathophysiological basis for the development of both type 2 diabetes and hypertension [28]. When the homeostasis model assessment of insulin resistance (HOMA-IR) was applied to estimate insulin resistance, it was revealed that the result was dramatically upregulated across the quartile levels of HbA1c in Korean males without diabetes [29]. Additionally, HbA1c was also reported to be one of the best indices for identifying insulin resistance in obese nondiabetic individuals [30]. Second, numerous studies have implied that HbA1c may play a role in arterial stiffness via proinflammatory cell signaling and oxidative stress [31,32]. It was demonstrated in a cross-sectional survey containing 11,014 Chinese participants that brachial–ankle pulse wave velocity and central SBP were markedly elevated across the quartiles of HbA1c [33]. Third, increased levels of HbAlc can contribute to endothelial damage that would further promote the release of endothelin from endothelial cells and inhibit the production of nitric oxide and prostacyclin, which would result in vasomotor dysfunction and further increase the BP [25,34]. Moreover, it has been reported that there is a direct association between HbAlc and the activation of the renin–angiotensin– aldosterone-system [35]. Also, it has been indicated in clinical research that blood lipids could be positively regulated by the high level of HbAlc, which contributed to the increase in blood viscosity and furthered the incidence of cardiovascular diseases [25]. With the increase in HbA1c level, the number of cardiovascular risk factors clustering, including fasting blood glucose, high total cholesterol, high TG, and high low-density lipoprotein cholesterol, was also dramatically upregulated [36].
To our knowledge, only a few studies have investigated the relationship between the HbA1c level and the risk of hypertension, and the conclusions were inconsistent. A cohort study of Americans including 9,603 participants demonstrated that higher baseline HbA1c concentrations were predominantly associated with the incidence of hypertension independently of obesity indices and other factors in diabetic as well as nondiabetic individuals [37]. Similarly, in a women’s health study, 19,858 American women initially without diabetes were followed up with for a median of 11.6 years. The subjects were grouped based on HbA1c by clinical quintiles, and the hazard ratio (HR) for the highest HbA1c quintile in comparison with that of the lowest was statistically significant in both the univariable analysis and multivariable analysis [38]. However, when grouping HbA1c by quintiles, the above significant association was eliminated after normalizing for BMI. Moreover, elevated HbA1c levels dramatically aggravated the risk of hypertension in an independent manner even after normalizing traditional risk factors in general middle-aged and elderly Chinese subjects [39]. Besides that, the Framingham Heart Study demonstrated that high HbA1c expression was associated with the prevalence of hypertension, but it was only based on a univariate analysis [40]. In a Japanese cohort study with five years of follow-up, 9,584 individuals were investigated, and elevated expressions of HbA1c were not associated with an increased risk of developing hypertension in the multivariable analysis [41]. An increment in HbA1c level was also reported not to be independently involved in the future development of hypertension among the Israeli population [42]. Kroke et al. [43] revealed that there was a nonsignificant relationship between HbA1c and arterial hypertension in nondiabetic participants; nevertheless, arterial hypertension was defined as a BP of 160/95 mmHg or greater. These inconsistencies may be explained by the diversity of HbA1c according to age, gender, and ethnicity.
Additionally, our results indicated a significant relationship between the HbA1c level and ISH risk but not IDH risk. Similarly, insulin resistance as indicated by TG–glucose index was suggested to be correlated with ISH risk rather than IDH risk [44]. In patients with type 2 diabetes, there was also an independent association between the duration of diabetes and ISH risk, suggesting that chronic hyperglycemia may play an essential role in the pathogenesis of ISH [45]. A cross-sectional investigation among middle-aged and elderly adults in China suggested that patients with ISH had a significantly higher prevalence of impaired glucose regulation and diabetes than those with IDH [46]. Overall, the prevalence of IDH was lower than that of ISH in hypertension subtypes. The distribution of hypertension subtypes was affected by various factors, such as economic level, gender, and age [47]. As is known, ISH independently reflects arterial stiffness and is more common in the elderly, while IDH is independently related to an increase in arteriolar resistance and is more common in young and middle- aged people. However, it should be considered that most of the subjects enrolled in this survey were middle-aged and elderly adults, and the number of cases of IDH in this study was relatively small. Therefore, the association between HbA1c and IDH risk needs to be further explored, especially in young adults.
This study further demonstrated that HbAlc plays a significantly interactive role in the impact of abdominal obesity rather than general obesity on the risk of hypertension. Several studies have suggested that abdominal fat distribution may be more strongly related to adverse outcomes, such as cardiovascular diseases, than BMI. It is well acknowledged that obesity is a predominant risk factor of hypertension [48]. When evaluating the predicted performance outcomes of different obesity indices on hypertension, WC was superior to BMI based on ROC curve analysis [49]. It was illustrated that obesity was dramatically associated with elevated HbA1c levels in diabetic as well as nondiabetic subjects. Obesity can lead to insulin resistance and result in poor glycemic control [25]. In addition, adipocytokines secreted from adipose tissue were involved in insulin resistance and beta cell dysfunction [50]. Furthermore, the occurrence of hypertension was a combinative consequence of genetic and environmental effects. A family history of hypertension was a simple and alternative genetic indicator. Moreover, a case–control study among Chinese individuals proved that a family history of hypertension and BMI had a positive impact on hypertension [17]. Our results also illustrated that HbAlc had a remarkable interaction with a family history of hypertension on the risk of hypertension.
There were several limitations in our study. First, the causality of the results failed to be inferred as this was a cross-sectional study. Second, the effects of different antihypertensive drugs on glucose metabolism varied but were not investigated in depth. However, it was shown that the effects of antihypertensive medication such as diuretics on HbA1c seemed to be of minor importance in diabetes as well as in nondiabetic individuals [51,52]. Third, BP was measured in a single session and may be influenced by various external factors.