This post-hoc analysis of a randomized clinical trial based on an unselected hospitalized population with AF showed that patients with concomitant DM exhibited higher mortality and morbidity rates and suffered more CV events compared to those without DM. To our knowledge, this is the first study to show that chronic glycemic status, represented along the continuum of HbA1c values, considerably predicted all-cause and CV death among patients with AF. HBA1c levels lower than 6.2% were independently associated with decreased risk of death.
DM was present in 1 out of 3 patients and this DM frequency ranks among the highest ones encountered in cohorts with AF patients, since only hospitalized patients were enrolled and not outpatients. The frequency of DM in our study population is almost equal to the one in the large ORBIT-AF registry6. The magnitude of association may differ between DM and each subtype of AF, with persistent/ permanent AF being most prevalent in our diabetic population. This was ascertained by other studies, such as EORP-AF7. Our results corroborate previous observations indicating that patients with AF and comorbid DM are older, more obese, and have a higher frequency of concomitant comorbidities, such as hypertension and impaired renal function than the non-diabetic ones7,12. Patients discharged with comorbid DM were also more likely to suffer from vascular or coronary artery disease, which is plausible due to DM being a major risk factor linked with these diseases13.
The intimate relationship of AF and DM is already known14,15 and the presence of DM is an established marker of worse prognosis, exerting negative impact on quality of life and increasing hospitalization rates in AF patients16,17. Similar to previous studies18, CV deaths were the most prevalent cause (more than 70% of all causes) of death in both diabetic and non-diabetic participants. Diabetic subjects had a 1.5-fold higher risk for all-cause death or CV death than the non-DM AF population, as well as 1.3-fold higher risk for the composite outcome of CV death or hospitalization during follow-up. These findings concur with those of the EORP-AF and ORBIT-AF studies, which demonstrated a nearly 2-fold higher risk of mortality in AF patients with comorbid DM, as compared to those without DM6,7. Additionally, the finding that DM patients under insulin and oral medication had worse prognosis than those solely on diet or lifestyle measures, is logically paralleled to the severity of DM encountered in the respective groups, as well as confounding factors.
Patients with DM did not exhibit a significant increase in hospitalizations for AF or HF related complications, in comparison with those without DM. This is in contrast to similar studies, in which DM significantly increased the long-term risk of hospitalization in patients with AF19,20. The analysis on major bleeding events did not correlate with the increased risk for bleeding in DM by the HAS-BLED score, possibly due to the sparse events. This may explain the inconsistency with other recent studies4,18.
Besides the current study, DM -and especially long-term DM- has been correlated with higher hazard for stroke in many recent studies5,21−24. However, the glycemic status of these patients seems to be the parameter determining their risk of stroke25, especially when DM lasts less than 10 years26. According to Chan et al. risk of stroke is significantly increased once HbA1c levels exceeded 6.5% in both diabetic and non-diabetic population with AF27. This correlation was not mirrored in our analysis, since higher HbA1c levels did not constitute an independent parameter for higher stroke incidence during the follow-up.
It is hypothesized that in AF with DM, the regulation of blood glucose levels could reduce the risk of mortality and adverse CV events. The association of poorly regulated blood glucose levels (HbA1c ≥ 8%) with more frequent adverse outcomes is already established in diabetic populations without AF28, whereas the present study is the first one to document a linear and positive association between the risk of CV or all-cause mortality and increases in HbA1c values in patients with AF and DM. Other observational studies on diabetic populations have suggested that both low and high HbA1c levels are associated with an increased risk of all-cause mortality (J or U shaped curves)28,29. The observation of increased mortality in extremely low HbA1c levels could not be ascertained in our analysis, maybe due to the limited number of patients with such values. In our study, lower HbA1c levels below a threshold of 6.2% were associated with lower risks of death. Additionally, despite the trend for increased mortality for HbA1c levels above 6.6% values, only values between 7.6 and 8.2% reached statistical significance in showing an increased risk of all-cause mortality.
Therefore, clinicians dealing with patients with AF and DM should view HbA1c levels as an indirect marker of long-term macrovascular risk with low intraindividual variability. Further research is requisite to bolster the prognostic value of HbA1c measurement in this subpopulation and prove whether specific intervention with HbA1c-targeted glycemic control can effectively improve survival. In spite of the guidelines available for the management of DM and AF patients, few work is representative of the unique AF-DM comorbidity30. Team work from experts across specialties, including cardiology and endocrinology, is needed to encapsulate the optimal approach for prevention and management of this dual comorbidity.