To the best of our knowledge, this study is the first investigation of the effectiveness of SGLT2 inhibitors in real-world patients with T2DM and AF. The main findings of this study are as follows: (1) patients treated with SGLT2 inhibitors did not have a significantly lower risk of MACE and its components compared with those treated without SGLT2 inhibitors; (2) the use of SGLT2 inhibitors was significantly associated with a lower risk of hospitalization for heart failure and all-cause mortality than the other hypoglycemic drugs; and (3) the benefits of SGLT2 inhibitors for hospitalization for heart failure were consistent across high-risk subgroups, including those with previous cardiovascular disease, previous heart failure, previous myocardial infarction, or high CHA2DS2-VASc scores (≥3).
In randomized cardiovascular outcome trials of SGLTs inhibitors, results regarding cardiovascular mortality and all-cause mortality were different depending on the type of SGLT2 inhibitor used.[2-5] A recent meta-analysis of three randomized trials using empagliflozin, canagliflozin, and dapagliflozin reported that SGLT2 inhibitors reduced the risks of cardiovascular mortality and all-cause mortality specifically in patients with established atherosclerotic cardiovascular disease. In a real-world cohort study, the use of SGLT2 inhibitors was associated with reduced cardiovascular mortality and all-cause mortality.[24, 25] In the present study, SGLT2 inhibitors use was associated with a significant reduction in all-cause mortality but not in cardiovascular mortality. Recently, two studies on Korean T2DM patients also reported that new users of SGLT2 inhibitors had a lower risk of all-cause mortality than those who received other hypoglycemic drugs;[19, 26] however, these studies did not evaluate the risk of cardiovascular mortality.[19, 26]
In the present study, we found a discrepancy in the effect of SLGT2 inhibitors for cardiovascular and all-cause mortalities. Unfortunately, we cannot explain the exact reason for this discrepancy, but we assume that the following mechanisms may be involved. First, the study patients were younger compared with those included in previous randomized trials on SGLT2 inhibitors[2-5] (59 years vs. 63–64 years) and had fewer cardiovascular therapeutics including antiplatelet agents, angiotensin-converting enzyme inhibitors, angiotensin-receptor blocker, beta-blocker, statin, and diuretics even though the prevalence of cardiovascular disease was not overtly different (53% vs. 40%–99%). Thus, the cardiovascular effect of SGLT2 inhibitors might be diminished in these patients with relatively low cardiovascular risks. Second, the number of cardiovascular deaths in the propensity score-matched cohort was too small to produce a statistically significant difference between treatment groups. Moreover, during the propensity score matching process, relatively fewer patients with cardiovascular risks were selected among the SGLT2 inhibitors group (54.5% vs. 51.1%), which might have led to the non-significant results for cardiovascular mortality. Finally, the pleiotropic effects of SGLT2 inhibitors on energy metabolism, lipid profile, uric acid, blood pressure, hematocrit, renin-angiotensin-aldosterone system, inflammation, and nitric oxide as well as hypoglycemia and weight reduction may have contributed to the reduced risk of all-cause mortality compared with other hypoglycemic drugs.[27, 28]
In the current study, the beneficial effect of SGLT2 inhibitors for hospitalization for heart failure was consistent with those reported in previous randomized trials and large population-based cohort studies.[2-4, 24, 25]  The incidences of hospitalization for heart failure were 0.6–0.9 per 100 patient-years in the SGLT2 inhibitor groups in previous randomized trials,[2-5] while it was 1.3 per 100 patient-years in this study. This difference might be due to the fact that we defined hospitalization for heart failure with a main or subsidiary diagnosis of heart failure, which led to a higher incidence of hospitalization for heart failure than those in previous randomized trials. When we defined the hospitalization for heart failure with the main diagnosis of heart failure, its incidence was 0.6 and 1.0 per 100 patient-years (HR, 0.56; 95% CI, 0.38 to 0.84; P=0.004) in the SGLT2 inhibitors group and the No SGLT2 inhibitors group, respectively. AF and heart failure share common risk factors and pathophysiology that lead to the development of the other condition,[30, 31]and patients with AF and heart failure have a poor prognosis. Individuals with T2DM showed a 2- to 4-fold increased risk of heart failure compared with those without in observational studies. Therefore, our results support the effectiveness of SGLT2 inhibitors for preventing hospitalization for heart failure in patients with T2DM and AF. The beneficial effect of SGLT2 inhibitors for hospitalization for heart failure was most evident in those treated with dapagliflozin, which is in line with the results of previous studies.[4, 33, 34] The effect of other SGLT-2 inhibitors was not evident in this study and should be further assessed in larger prospective studies.
This study has several limitations and our results should be interpreted with caution. First, because this was a retrospective observational study using the NHIS database, we could not ascertain specific clinical data such as the duration, glucose control status, or severity of T2DM,the duration, type (paroxysmal, persistent, or permanent), or rhythm status of AF as well as laboratory data such as HbA1c, brain natriuretic peptide and echocardiographic data. Second, there could be selection bias and residual confounding factors, but we tried to overcome these limitations by using propensity score matching patients with SGLT2 inhibitors and without SGLT2 inhibitors. Thirdthe study population was a homogeneous group of Korean ethnicity, so caution is required when generalizing the findings of this study to other ethnic groups. Fouth, as we defined cardiovascular outcomes using ICD-10 codes, there is a possibility of outcome misclassification. However, a recent study comparing diagnoses from claims databases with medical records showed that the overall accuracy rates were 92.0% for myocardial infarction and 90.5% for ischemic stroke. Thus, we believe that misclassification of study outcomes might be low and would not have significantly affected the main results. Fifth, we were not allowed to evaluate the specific prescription or dose of medication including SGLT2 inhibitors and other hypoglycemic drugs because NHIS policy has changed not to provide an information about specific brand name drug. So, we could not compare the effectiveness of each SGLT2 inhibitors vs other hypoglycemic drugs. And also, we did not have information about use of metformin for reasons mentioned above. However, there would be no significant difference of metformin prescription between two study groups because SGLT2 inhibitors or the other hypoglycemic drugs had health insurance coverage as secondary hypoglycemic drugs after metformin for T2DM patients. In addition, we could not incorporate the effect of medication compliance in our analysis. Finally, this study had a relatively short follow-up duration (2.1 ± 1.4 years). Thus, further studies are needed to evaluate the long-term effects of SGLT2 inhibitors in patients with T2DM and AF. Despite these limitations, this study has the strength of being a nationwide study with large sample size. Furthermore, to the best of our knowledge, this is the first and the largest Asian study to report the cardiovascular effects of SGLT2 inhibitors in real-world patients with T2DM and AF.