In this large-scale nationwide cohort study, we compared the cardiovascular benefits of dapagliflozin and empagliflozin in a real-world setting. Over 70,000 respective dapagliflozin and empagliflozin users were included, with a median follow-up of > 150,000 PY. To the best of our knowledge, this is the largest population-based cohort study comparing the efficacy of different SGLT2 inhibitors. We demonstrated several key findings. (1) The risk of composite cardiovascular outcomes of heart failure-related events, ischemic stroke, MI, and cardiovascular death was similar. However, female dapagliflozin users appeared to benefit more. (2) Dapagliflozin use was associated with significantly lower risks of heart failure-related events and cardiovascular death, whereas the risks of ischemic stroke and MI were similar. (3) The risks regarding the safety outcomes were similar in both groups. These results were consistent in the main intention-to-treat analysis and the as-treated sensitivity analyses.
Comparison with previous studies and interpretation
Previous meta-analyses encompassing large CVOTs have demonstrated that both dapagliflozin and empagliflozin have favorable composite cardiovascular outcomes of cardiovascular death, MI, and ischemic stroke, as well as hospitalization for heart failure over placebo in patients with T2DM [
16,
17,
34,
35]. No significant difference was observed across the medication classes, whereas some heterogeneity was presented regarding individual outcomes. As highlighted by Darren et al., however, the patient characteristics of these trials differed notably; thus, comparing dapagliflozin and empagliflozin based on these trials might be limited [
2‐
4,
16]. In particular, when comparing the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) trial to the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose) trial, it should be noted that the latter included patients with much more comorbidities [
2,
4]: even between the placebo groups of both studies, composite cardiovascular outcomes and cardiovascular death were two-fold and three-fold higher, respectively, in the EMPA-REG OUTCOME trial. In addition, since previous meta-analyses aggregated study-level data, they might be less appropriate to compare two medications at an individual level [
16,
17,
34,
35]. In contrast, in Korea, both medications are approved for use in the same medical condition and are covered by medical insurance, resulting in a negligible difference in the actual cost paid by patients (< $10 per year). Consequently, which medication to prescribe is entirely at the individual physician’s discretion. More so, the baseline characteristics of both groups could have been similar even prior to PS matching. Therefore, this study might be advantageous when comparing the efficacies of both drugs.
Compared to previous meta-analyses that suggested no discernible difference among different SGLT2 inhibitors, this study showed that dapagliflozin might have similar but slightly favorable composite cardiovascular outcomes compared to empagliflozin and significantly lower risks of cardiovascular death and heart failure-related events [
16,
17,
34,
35]. These findings might be attributed to significant differences in the study population. Large CVOTS encompassed in meta-analyses comprised mostly white males but fewer females and Asian ethnic groups. For instance, Asians comprised approximately 13.5% and 21.5% in the DECLARE-TIMI 58 and EMPA-REG OUTCOME, respectively. The mean age in both trials was 63–64 years, women comprised about 37% and 28%, and the mean BMI was 30.6 and 32.0 kg/m
2, respectively. Conversely, the entire study population in our cohort was Asian. Women comprised 42%, and the mean BMI was 26.9 kg/m
2. Most importantly, our study included a general T2DM population, and nearly two-fifths had low cardiovascular risks, whereas the aforementioned CVOTs included a highly selective population of T2DM patients with multiple cardiovascular risk factors or established cardiovascular diseases. Specifically, in the EMPA-REG OUTCOME trial, ≥ 75% of the study participants had evidence of ischemic heart disease, and nearly 25% had a documented history of stroke [
2]. As a result, our study’s incidence rate for the composite of cardiovascular death, MI, and ischemic stroke was 6.03–6.44/1,000 PY—far lower than the 22.6/1000 PY of DECLARE-TIMI 58 or 37.4/1000 PY of EMPA-REG OUTCOME—demonstrating the significant difference in the study population. Accordingly, these differences might explain our novel findings. More importantly, given its substantial sample size associated with real-world data, our study can more accurately reflect actual clinical practice.
Meanwhile, a retrospective cohort study conducted in Taiwan showed consistent results with our findings with 12,681 new users of dapagliflozin or empagliflozin, i.e., similar risks of composite cardiovascular outcomes and a significantly lower risk of heart failure in dapagliflozin users [
36]. Cardiovascular death in this Taiwanese study was also lower in the dapagliflozin group (HR 0.54, 95% CI 0.14–2.12). However, the difference was not significant, probably due to few events considering the wide CI. With a larger sample size, our study might corroborate the trend of a lower risk of cardiovascular death in the dapagliflozin group observed in the Taiwanese study. These consistent results are hypothesis-generating that dapagliflozin might have a drug-specific effect on Asians. Future studies are needed to identify associations between ethnic, cultural, or lifestyle differences and the pharmacokinetics and pharmacodynamics of dapagliflozin and empagliflozin.
As the SGLT2 inhibitor arm was superior to the placebo in terms of heart failure hospitalization and cardiovascular death in landmark clinical trials, it is intriguing to note that significant differences between users of dapagliflozin and empagliflozin were observed only for these two outcomes [
2‐
4,
12‐
17]. This may allude to intrinsic disparities between the two drugs and could lead us to posit that dapagliflozin may exert more pronounced pleiotropic effects on heart failure outcomes than empagliflozin. For example, different neurohormonal responses might be one of the possible mechanisms. A previous study revealed that empagliflozin significantly increased plasma aldosterone and noradrenaline levels; however, dapagliflozin did not [
37]. It was also noted that the change in plasma volume is a key mediator in reducing cardiovascular death among users of SGLT2 inhibitors [
38]. Taken together, different neurohormonal responses and the concomitant reductions in plasma volume might synergistically contribute to the further decrease in the risk of heart failure-related events and cardiovascular death in dapagliflozin users. On the other hand, neurohormonal responses may not affect ischemic endpoints such as MI or ischemic stroke, as SGLT2 inhibitors have been found to be independent of pathways governing arterial thrombosis [
39]. This is further supported by the pronounced advantages observed in women. Specifically, in our subsequent analysis, the cardiovascular benefits were evident only in women > 50 years. Although individual menopausal status could not be noted, women > 50 years, who were mostly in their peri- or post-menopausal stage and, hence, more susceptible to changes in neurohormones and plasma volume, would have benefited more from dapagliflozin and showed improved cardiovascular outcomes [
40]. Secondly, the approximate 2.5-fold greater affinity for SGLT2 and six-fold greater affinity for SGLT1 exhibited by dapagliflozin compared to empagliflozin might have contributed [
41]. Currently, the benefits of adding SGLT1 to SGLT2 inhibition are receiving attention. A study with Mendelian randomization data revealed that patients with missense mutations in the SGLT1 gene had reduced risks of heart failure and death [
42]. Recent clinical trials, SOLOIST (effect of sotagliflozin on cardiovascular events in patients with type 2 diabetes post worsening heart failure) and SCORED (effect of sotagliflozin on cardiovascular and renal events in patients with type 2 diabetes and moderate renal impairment who are at cardiovascular risk), also raised the possible advantage of additional SGLT1 inhibition for cardiovascular outcomes [
43,
44]. Accordingly, the higher SGLT1 and SGLT2 affinity of dapagliflozin compared to that of empagliflozin might contribute to the lower risks of heart failure-related events and cardiovascular death in our study. In addition, several studies have suggested that the SGLT2-independent effects of this drug class, which are presumed to take place in the myocardium, are likely attributed to off-target effects, given the notably low levels of SGLT2 in cardiac cells [
45]. Further investigations focusing on differences in off-target effects between dapagliflozin and empagliflozin are needed.