In this large case-control study based on primary care data from the UK, patients with HbA1c > 7.0% (> 53 mmol/mol) did not have an increased risk of unprovoked VTE compared to patients with HbA1c > 6.5-7.0% (> 48–53 mmol/mol). In the subset of female patients, we found a suggestion of a slightly increased risk of VTE in women with HbA1c > 7.0% (for example HbA1c > 7.5-8.0%: aOR 1.24, 95% CI 1.03–1.50) when compared to those with HbA1c > 6.5-7.0% (> 48–53 mmol/mol). This increase was slightly more pronounced if we only considered patients with HbA1c measurements taken within 90 days prior to the index date. Overall, however, the association in women was weak, and there was no trend of increasing risk of VTE in association with increasing HbA1c values. We did not observe an increased risk of VTE in men at any level of glycemic control.
The weak association between elevated HbA1c levels and risk of VTE in women, but not in men, may be explained by the fact that pre-diabetic and diabetic women are more affected by chronically elevated cardiovascular risk factors, and their health declines faster when compared to men. [22, 36, 37]. Since T2DM is a disease with uncertain onset, which can remain undiagnosed for many years, this difference in risk factor levels between men and women is relevant. Several studies, including a comprehensive meta-analysis, suggest that the presence of diabetes eliminates the biological female advantage that is often used to explain the lower absolute rates of coronary heart disease (CHD) and stroke in women compared to men.[22, 38, 39] The authors of this meta-analysis estimate that the relative risk for CHD is 44% greater in women with diabetes than in similarly affected men. In general, our study population included more women than men, even though men are more often affected by T2DM and by VTE, when the diseases are observed independently of each other. The T2DM cohort for our study also included more men than women prior to the identification of the VTE cases (50.8% vs 49.2%). Several studies provide an explanation for this imbalance in the rates of affected females and males by showing that adverse changes in metabolic and vascular risk factor profiles are greater in women than in men. These changes occur in diabetic individuals as well as earlier in pre-diabetic individuals.[15, 22–24]
Patients with CVD and HbA1c levels > 7.0% (> 53 mmol/mol) did not have an increased risk of VTE when compared to those with HbA1c levels between > 6.5-7.0% (> 48–53 mmol/mol), though women with CVD and HbA1c level > 7% (> 53 mmol/mol) had a slightly elevated risk for VTE, while men with CVD did not. This result emphasizes the general importance of proper glycemic control in women suffering from both, CVD and T2DM.
In our study, patients with no recorded HbA1c measurements had a higher risk of VTE compared to patients with HbA1c > 6.5-7.0% (> 48–53 mmol/mol) throughout our analyses. This could be a proxy for a lack of patient-doctor interaction and poor treatment adherence, which could lead not only to a higher risk for VTE (as suggested in this study), but potentially to other complications caused by improper management of T2DM.
The present findings should be interpreted within the context of the strengths and limitations of an observational study. A delayed diagnosis of T2DM may have led to the inclusion of some prevalent (instead of incident) T2DM cases in our cohort. Additionally, the UK Prospective Diabetes study found that a high prevalence of DM tissue damage was already present by the time the DM diagnosis was made, which is an indication of pre-existing DM. Therefore, we may have underestimated the time until VTE events (after the recorded DM diagnosis) in our study population, which could have potentially affected our matching on DM duration. However, this misclassification is unlikely to have been differential by HbA1c level, and we do not expect that it had a major influence on our findings.
Though VTE events are well recorded and have previously been validated in the CPRD (positive predictive value 88.2% [82.3–92.6%] for VTE), it is possible that we missed some unrecorded VTEs. This possible misclassification would likely be non-differential and would not materially change the results.
The strengths of our study include the large study sample and the observational nested case-control design within a cohort of patients with newly diagnosed T2DM. Our data come from a well validated primary care database that contains prospectively and routinely collected data, which avoids recall bias. Even though we only used the last HbA1c measurement before the index date, HbA1c measurements are regularly performed in the diabetic population, and median time between the index date and the last HbA1c measurement was short. This shows that the recorded HbA1c measurements provide a reliable and timely source for our analyses on the effect of glycemic control on the risk of VTE.
Our study population included a high proportion of patients with T2DM with HbA1c ≤ 7% (> 53 mmol/mol) who may have been healthier than the T2DM populations analyzed in other studies. Nevertheless, our population consisted of over 19’480 patients with T2DM, many of whom had HbA1c levels > 7% (> 53 mmol/mol). Therefore, we expect our results to be generalizable to those of other populations with T2DM and HbA1c levels > 7% (> 53 mmol/mol).
In conclusion, our study provides evidence that HbA1c levels > 7% (> 53 mmol/mol) are not associated with a materially increased risk for unprovoked VTE overall. There was a suggestion of a slightly increased VTE risk in women, which may be real or may reflect differences in lifestyle or other patient characteristics.