In this large community-based prospective study, higher HbA1c values at baseline were associated with increased risk of hypertension during long-term follow-up. This association was independent of known risk factors and was observed for HbA1c values even below the diagnostic threshold for diabetes. Poor glycemic control also was associated with increased risk of hypertension among those with diagnosed diabetes. The associations were similar for both of the hypertension definitions used, although our findings were more robust for the self-reported hypertension outcome as compared with the visit-based definition, perhaps because of increased statistical power (5,177 self-reported vs. 1,789 visit-based hypertension cases). Adjustment for measures of adiposity strongly attenuated the observed association, suggesting that obesity may partially explain the higher risk of hypertension among individuals with hyperglycemia. Nonetheless, a significant effect of elevated HbA1c on hypertension risk remained even after adjustment for multiple risk factors and two measures of adiposity.
Few prospective studies have examined the association between HbA1c
and subsequent hypertension risk. However, previous studies have reported positive associations between hyperglycemia and blood pressure levels (27
), although some of these associations were weak or not statistically significant (31
). In addition, previous studies have shown a more favorable blood pressure profile among individuals with diabetes receiving glucose-lowering treatment (19
). Our findings are of similar magnitude to results from the Women’s Health Study reported by Britton et al. (27
), which reported an association between HbA1c
and risk of self-reported hypertension that was similarly attenuated after adjustment for BMI. However, the Women’s Health Study relied on self-report only and did not have information on measured blood pressure to identify undiagnosed cases of hypertension.
The association between hyperglycemia and hypertension may reflect the presence of shared risk factors, particularly adiposity. In addition, inflammatory processes have been implicated in both the development of hyperglycemia and hypertension (32
). However, several potential mechanisms may explain why higher HbA1c
values predict the development of hypertension. Because hyperglycemia leads to high glucose flux across endothelial cell membranes (33
), the resulting increased oxidative stress reduces the bioavailability of nitric oxide and contributes to endothelial dysfunction that may subsequently alter blood pressure (11
). Furthermore, previous evidence suggests that hypertension risk may be elevated in those with higher levels of circulating glucose via increased systemic vascular resistance and stiffness (10
). Excess circulating glucose also may bind proteins, lipids, and nucleic acids, resulting in the formation and accumulation of advanced glycation end products (36
); accumulation of advanced glycation end products in the vessel wall may contribute to inflammation, oxidative stress, and endothelial dysfunction.
There are certain limitations of this study that should be considered in the interpretation of the results. Only a single measurement of HbA1c at baseline was available, which may have resulted in misclassification. Future analyses with additional measurements of HbA1c may reveal stronger associations with incident hypertension. Furthermore, despite rigorous measurement of cardiovascular risk factors, we cannot rule out the possibility of residual confounding in this observational study. In particular, we observed that the association was attenuated after adjustment for BMI and waist circumference; it is possible that adjusting for these measures did not fully account for potential confounding by adiposity. In addition, although we excluded individuals with prevalent hypertension at baseline to establish the directionality of the association between hyperglycemia and hypertension, the causal relationship remains unclear. Finally, some analyses may have had limited power to detect small to moderate effects (e.g., we had only 119 incident visit-based hypertension cases among those with diagnosed diabetes at baseline). Nonetheless, our study benefited from the large sample size and both measured blood pressure and self-reported information to identify cases of hypertension during a long duration of follow-up.
In summary, we found a positive association between elevated HbA1c at baseline and incident hypertension, suggesting that hyperglycemia may play a role in the development of hypertension even in individuals without a prior history of diabetes. In particular, HbA1c in the prediabetic range and HbA1c ≥7.0% among those with diagnosed diabetes (i.e., those with poorer glucose control) were independently associated with incident hypertension. Combined with evidence demonstrating that HbA1c is a marker of long-term cardiovascular risk, our results suggest that individuals with elevated HbA1c, even in the absence of diabetes, are at increased risk for hypertension and should be targeted for cardiovascular risk factor management and hypertension prevention strategies.