Heart and kidney outcomes with dapagliflozin versus empagliflozin in type 2 diabetes patients without previous heart or kidney disease

Patients with type 2 diabetes prescribed empagliflozin, dapagliflozin, or a dipeptidyl peptidase-4 inhibitor (DPP4i) at Seoul National University Bundang Hospital from April 2009 to December 2020 were retrospectively identified [27]. The date of medication (SGLT2i or DPP4i) initiation was defined as the index date. Exclusion criteria were type 1 diabetes mellitus, prior HF, prior ASCVD (angina, myocardial infarction, coronary revascularization, peripheral artery disease, and stroke), prior CKD (glomerular filtration rate [GFR] <45 mL/min/1.73m²), short duration of medication use (<3 months), low medication possession ratio (<75%), and simultaneous or sequential use of empagliflozin and dapagliflozin.

In total, 921 patients treated with empagliflozin, 1,424 patients treated with dapagliflozin, and 10,981 patients treated with DPP4i (control group) were identified (Fig 1). After propensity-score matching (1:1:2 ratio) on clinical factors, laboratory findings, and medication use, the empagliflozin and dapagliflozin groups comprised 921 patients each, and the DPP4i (control) group comprised 1,842 patients (Fig 1 and S1 Appendix). The Institutional Review Board of Seoul National Bundang Hospital approved the study protocol and waived the requirement for informed consent.

We collected data on age, sex, systolic blood pressure, diastolic blood pressure, history of smoking, preexisting comorbidities, 10-year ASCVD risk, medications, and laboratory findings, including the lipid profile, fasting glucose level, glycated hemoglobin A1c (HbA1c) level, and GFR. The 10-year ASCVD risk among patients without pre-existing cardiovascular disease was calculated by using the Pooled Cohort Equations, with consideration of age, sex, total cholesterol, low-density lipoprotein cholesterol (LDLc), systolic blood pressure, treatment of high blood pressure, diabetes, and smoking status, according to the American College of Cardiology/American Heart Association guidelines [28, 29].

Study outcomes comprised composite coronary events (acute coronary syndrome and coronary revascularization), composite ischemic events (acute coronary syndrome, coronary revascularization, and stroke), hospitalization for HF (HHF), renal events (renal death, initiation of renal replacement therapy, and admission due to acute kidney injury or CKD progression), and composite HHF and renal events. Changes in the levels of total cholesterol, LDLc, and HbA1c, and GFR during follow up were also assessed.

To adjust for imbalances in the baseline characteristics of patients among empagliflozin, dapagliflozin, and control groups, propensity-score matching, with a 1:1:2 ratio, was performed using the nearest neighbor method, with the following covariates: age, sex, 10-year ASCVD risk, systolic blood pressure, presence of microalbuminuria/proteinuria, HbA1c level, GFR, and the use of antiplatelet agents, renin-angiotensin system blockers, and statins. The distributions of propensity scores and standardized mean differences were calculated to assess the strength of matching.

Categorical variables are presented as numbers with percentages, and continuous variables as medians with interquartile ranges (IQRs). Group comparisons were performed using the χ2 test for categorical variables and analysis of variance for continuous variables. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using the Cox proportional-hazards method. Statistical analyses were performed using SPSS version 22.0 (IBM Co., Armonk, NY, USA) and R version 4.0.2 (The R Foundation for Statistical Computing, Vienna, Austria). Two-sided p-values <0.05 were considered statistically significant.

The baseline characteristics, laboratory findings, and use of medications were well balanced among the groups (Table 1). The median age was 56, 56, and 57 years in the dapagliflozin, empagliflozin, and control groups, respectively, and two-thirds of the patients were male. The prevalence of current smoking, hypertension, and dyslipidemia was 20%, 60%, and 80%, respectively. The mean 10-year ASCVD risk ranged 10%–11%, without significant inter-group differences. In all three groups, the median HbA1c level was approximately 8.0% and median GFR was approximately 97 mL/min/1.73m², and the prevalence of microalbuminuria or proteinuria was more than 30%. Two-thirds of the patients were on statins, and less than 50% were on renin-angiotensin system blockers. Regarding anti-diabetic medication, more than 97% of the patients were on metformin, more than 40% were on sulfonylurea, and 18% were on insulin therapy.

The median follow-up duration was 37.3 months (IQR, 24.5–55.7 months), 37.1 months (IQR 27.1–49.2 months), and 55.1 months (27.5–84.9 months) in the dapagliflozin, empagliflozin, and control groups, respectively (Table 2). Composite coronary events occurred in 6 patients (0.7%) in the dapagliflozin group, 10 patients (1.1%) in the empagliflozin group, and 55 patients (3.0%) in the control group. On multivariable analysis, advanced age, current smoking, presence of hypertension, and higher 10-year ASCVD risk were associated with a higher risk of composite coronary and ischemic events (Table 3). SGLT2i use was significantly associated with a lower incidence of composite coronary events (dapagliflozin vs. control: HR, 0.267; 95% CI, 0.114–0.627; p = 0.002) (empagliflozin vs. control: HR, 0.467; 95% CI, 0.235–0.929; p = 0.030), without a significant difference between dapagliflozin and empagliflozin groups (HR, 2.196; 95% CI, 0.742–6.502; p = 0.156) (Fig 2A). Likewise, compared to that in the control group, the occurrence of composite ischemic events was significantly less frequent in the dapagliflozin group, and tended to be lower in the empagliflozin group, without a significant difference between dapagliflozin and empagliflozin groups (Fig 2B).

Composite HHF and renal events occurred in 4 patients (0.4%) in the dapagliflozin group and 8 patients (0.9%) in the empagliflozin group (Table 2). Significant risk factors for HHF and renal events comprised atrial fibrillation, impaired renal function, and the presence of microalbuminuria or proteinuria (Table 4). Both dapagliflozin and empagliflozin demonstrated significant beneficial effects against HHF and renal events compared to that with DPP4i (dapagliflozin vs. control: HR, 0.186; 95% CI, 0.067–0.516; p = 0.001) (empagliflozin vs. control: HR, 0.358; 95% CI, 0.169–0.756; p = 0.007) (Fig 3).

Changes in the levels of total cholesterol, LDLc, and HbA1c, and GFR during follow up are shown according to group in Fig 4. At baseline, there were no significant inter-group differences in the levels of total cholesterol, LDLc, and HbA1c, and GFR. Overall, the total cholesterol level did not show inter-group differences during follow up (Fig 4A). However, at 24 and 36 months of treatment, the LDLc level was significantly higher in the empagliflozin group than in the control and dapagliflozin groups (Fig 4B), and the HbA1c level was significantly lower in the empagliflozin group than in the other groups (Fig 4C). Additionally, the GFR level tended to be better preserved at 24 months of treatment, and was significantly higher at 36 months and 48 months of treatment, in the dapagliflozin and empagliflozin groups than in the control group (Fig 4D).

A series of landmark trials provided robust evidence on the cardiovascular and renal benefits of SGLT2i, regardless of baseline ASCVD status. In the EMPA-REG outcome trial, empagliflozin was associated with a reduced risk of cardiovascular death (HR, 0.86; 95% CI, 0.74 to 0.99; p = 0.04 for superiority) in patients with type 2 diabetes and established ASCVD [6]. Canagliflozin showed a reduced risk for HHF and cardiovascular death (HR, 0.78; 95% CI, 0.52–0.87; p = 0.02) and composite renal outcomes (HR, 0.60; 95% CI, 0.47 to 0.77; p<0.001) in patients with type 2 diabetes, two-thirds of whom had established ASCVD [3, 4]. In the DECLARE–TIMI 58 trial, dapagliflozin showed a lower rate of cardiovascular death and HHF compared to that with placebo in patients with type 2 diabetes with established ASCVD (40%) or at high risk for ASCVD (60%) (HR, 0.83; 95% CI, 0.73–0.95; p = 0.005) [5]. In a meta-analysis, SGLT2i use was associated with a reduced risk of major adverse cardiovascular events, HHF, and adverse kidney outcomes, independent of baseline ASCVD status [30].

Furthermore, the benefits of SGLT2i use have been observed in patients without prior cardiovascular disease, HF, or CKD. In the EMPRISE East Asia study, empagliflozin treatment was associated with a 28% reduced risk for HHF in diabetic patients without cardiovascular disease [31]; SGLT2i use showed a 36% risk reduction for HHF among diabetic patients without prior HF [32]; and SGLT2i use resulted in a 30%–40% reduction in the risk of HHF and 40%–50% reduction in the risk of adverse renal outcomes among diabetic patients with GFR ≧60 mL/min/1.73m² [33]. These findings support the benefits of SGLT2i for primary prevention in patients with type 2 diabetes but without overt ASCVD, HF, or CKD.

The benefits of SGLT2i observed in clinical trials can be explained by multiple mechanisms, beyond the glucose lowering effect: improvement in ventricular loading condition by natriuresis and osmotic diuresis, improvement in cardiac metabolism, reduced myocardial necrosis and fibrosis, and restoration of tubuloglomerular feedback [10, 11]. In addition, the pleiotropic effects of SGLT2i include benefits on endothelial function by attenuating oxidative stress and inflammation, and reductions in plaque size and vulnerability, as shown in preclinical and clinical studies [14, 34].

Given the concordant benefits of various SGLT2i, as well as their similar pharmacologic profiles, a class effect has been suggested for this drug entity. Although there have been some discrepancies in the reported clinical outcomes in clinical trials, this can be explained by differences in the inclusion criteria, baseline characteristics, and outcome definitions. However, several studies have suggested that SGLT2i effects may differ according to drug type. According to a multi-institutional cohort study by Shao et al., dapagliflozin may offer a more favorable benefit in terms of HF prevention, compared to that with empagliflozin [19]. In another study by Shao et al., dapagliflozin had a more favorable HHF risk reduction than empagliflozin in patients with type 2 diabetes without ASCVD, while similar HHF risks were observed in patients with type 2 diabetes with ASCVD [20]. The more potent effects of dapagliflozin over empagliflozin for HF outcomes can be explained by the SGLT2:SGLT1 receptor selectivity ratio, which is lower for dapagliflozin (1200:1) than for empagliflozin (2500:1) [35, 36]. More specifically, myocardial ischemia and hypertrophy are associated with SGLT1 upregulation in the myocardium, where SGLT2 receptors are never expressed. This finding suggests that the SGLT2i with a lower specificity for SGLT2 receptors, and thus, a greater effect on SGLT1, has an even greater beneficial effect on HF prevention [37]. In addition, compared to that with empagliflozin, dapagliflozin did not increase plasma aldosterone and noradrenaline levels, which could be advantageous for HF prevention [38].

In the present study, the benefits for HF and renal outcomes did not differ between dapagliflozin and empagliflozin groups, showing consistently lower event rates compared to the DPP4i group. The changes in GFR also demonstrated similar patterns for these two SGLT2i, which showed significant benefits over DPP4i treatment (control group). These findings infer that the use of SGLT2i, regardless of subtype, provides consistent benefits on HF and renal outcomes, suggesting the presence of class effect of SGLT2i. Of note, in contrast to the studies by Shao et al. [19, 20], we did not observe a more favorable benefit with dapagliflozin than with empagliflozin in terms of HF and renal outcomes. However, we acknowledge that the present study had a relatively small sample size and was performed in a retrospective manner. Although our findings support a SGLT2i class effect on HF and renal outcomes, future studies are warranted to compare their effects in a prospective trial or using nationwide real-world data.

Regarding the risk of ischemic events, a prospective observational study by Ku et al. found that empagliflozin resulted in better glycemic control and improvements in cardiometabolic components than that with dapagliflozin among patients with type 2 diabetes [21, 22]. Similarly, in the present study, we found that HbA1c levels tended to be lower in the empagliflozin group than in the dapagliflozin and control groups. However, better glycemic control with empagliflozin was not associated with clinical benefits: the risk of composite coronary and ischemic events was not significantly different between the two SGLT2i groups. Rather, the LDLc levels at 24 and 36 months were significantly higher in the empagliflozin group than in the other groups. This might be a reason for the slightly higher rates of ischemic events in the empagliflozin group than in the dapagliflozin group. Considering that a high LDLc level is a well-established risk factor for cardiovascular events, the possible association between a worse lipid profile and numerically higher rates of ischemic events in the empagliflozin group should be clarified in future clinical trials.

Nonetheless, given the similar clinical outcomes between dapagliflozin and empagliflozin in the present study, as well as the concordantly better outcomes with both SGLT2i compared to that with DPP4i, the present findings support a SGLT2i class effect. Indeed, current guidelines recommend both SGLT2i and DPP4i, equally, as second-line antidiabetic medication in diabetic patients without high ASCVD risk or established ASCVD, CKD, or HF [2]. Considering the characteristics of the present cohort, which comprised diabetic patients with intermediate ASCVD risk, but without established ASCVD, CKD, or HF, the present findings suggest that the use of SGLT2i is preferred even in this population. Further, our results support the pleiotropic effects of SGLT2i for ASCVD prevention, that are independent of the management of glucose and lipid profile.

First, due to the relatively small sample size with a short follow-up duration, the number of clinical events might not have been adequate to demonstrate a difference between dapagliflozin and empagliflozin. This may also be related to the characteristics of the study population, in which patients with prior ASCVD, CKD, or HF were excluded. Thus, the interpretation of the present findings requires caution, and further studies are needed to assess the comparative effects of dapagliflozin, empagliflozin, and other SGLT2i in higher-risk populations over a longer study period. Second, laboratory tests were not performed with pre-specified schedules due to the retrospective nature of the study. However, more than 16,000 laboratory test results were included in the analysis, suggesting that our findings reflect real-world clinical practice. Third, although we used propensity-score matching to minimize differences in baseline characteristics between groups, some unmeasured confounders might remain unresolved.

Dataset for this study was provided in the(). Supporting Information S1 Appendix