This section reviews current evidence regarding SGLT2i effects on MACE, HF, HTN, AF, and CKD, with detailed findings of trials discussed in Tables 1 and 2.

Large-scale clinical trials have shown that some SGLT2i reduce MACE in patients with T2DM, particularly those with established CV or renal disease.

The EMPA-REG OUTCOME trial showed a significant reduction in MACE with empagliflozin, driven by a reduction in the risk of CV death among patients with T2DM and established CVD [4]. The CANVAS Program also found reductions in CV death and nonfatal MI with canagliflozin, though not in nonfatal stroke [5]. In the DAPA-HF trial, dapagliflozin reduced CV death and showed favorable trends in MACE despite not being powered for this composite [9]. This was further explored with the DECLARE-TIMI 58 trial found that dapagliflozin did not significantly lower MACE overall, but did reduce hospitalizations for HF and improve renal outcomes [6]. Similarly, the VERTIS-CV trial confirmed the CV safety of ertugliflozin but showed no significant superiority in MACE outcomes [7]. Real-world data from the SGLT2-I AMI PROTECT Registry support these findings, showing a significant reduction in MACE in patients with T2DM hospitalized for MI and treated with SGLT2i [8].

Additional CV outcomes trials, although primarily focused on HF endpoints, offer further insight into MACE outcomes. Empagliflozin significantly reduced the combined risk of CV death or hospitalization for HF in patients with heart failure with reduced ejection fraction (HFrEF). However, the reduction in CV death alone was not statistically significant [10].

SGLT2i have also been studied in patients with CKD and other high-risk groups. The CREDENCE trial, though focused on renal endpoints, found a significant reduction in MACE with canagliflozin in patients with diabetic kidney disease [11]. This trial was important because it confirmed that SGLT2i could reduce CV risk in patients with advanced diabetic kidney disease. Similarly, the SCORED trial, which enrolled patients with T2DM and CKD, observed a significant reduction in MACE, though this was no longer the primary endpoint at study conclusion [12].

While not all SGLT2i have indicated uniform effects on MACE, the overall evidence supports a clinically meaningful reduction in CV events, especially in patients with T2DM and established CV or renal disease. Whether SGLT2i reduce single endpoints like MI, or more specifically ST-segment elevation MI (STEMI), is a topic of ongoing research. Some of the challenges to this include competing background therapies in populations of interest, diversity of MI subtypes, and overall time-course of atherosclerotic disease progression. Nonetheless, consistent trends in CV death and MI across multiple studies suggest that SGLT2i may contribute to broader cardioprotection in appropriately selected patients.

Key Point: Large-scale clinical trials have shown that some SGLT2i reduce MACE in patients with T2DM, particularly those with established CV or renal disease.

The role of SGLT2i in HF has been extensively studied across a spectrum of patient populations, including those with and without T2DM and across both reduced and preserved ejection fraction phenotypes. Initial CV outcome trials such as EMPA-REG OUTCOME and DECLARE-TIMI 58 provided important insights, showing significant reductions in hospitalization for HF among patients with T2DM at high CV risk treated with empagliflozin and dapagliflozin, respectively [4, 6].

Subsequent trials directly targeting patients with established HF further clarified their therapeutic role. The DAPA-HF trial demonstrated a significant relative risk reduction in the composite outcome of worsening HF or CV death with dapagliflozin in patients with HFrEF, regardless of diabetes status [9]. Similarly, the EMPEROR-Reduced trial showed a significant reduction in this same composite outcome with empagliflozin in patients with HFrEF, alongside significant renal benefits [13]. These findings solidified SGLT2i as a cornerstone therapy in HFrEF management.

In patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF and HFpEF), the EMPEROR-Preserved trial was the first to demonstrate a significant relative risk reduction in the composite of CV death or HF hospitalization with empagliflozin [10]. More recently, the DELIVER trial expanded these benefits to patients with HFmrEF and HFpEF with dapagliflozin [14]. These findings suggest the effects of SGLT2i in reducing HF morbidity extend across a broad range of HF phenotypes.

Sotagliflozin, a dual SGLT1/SGLT2 inhibitor, has also demonstrated efficacy in HF. In the SOLOIST-WHF trial, patients with T2DM and recently decompensated HF treated with sotagliflozin had a significantly reduced risk of CV death and hospitalizations [15]. Notably, sotagliflozin is now approved in the USA for HF, with proposed mechanisms that extend beyond natriuresis, including modulation of intestinal glucose absorption and improved cardiac metabolism.

Key Point: Large-scale clinical trials have shown that SGLT2i reduce rates of CV death and HF hospitalizations in patients with HF regardless of ejection fraction or glycemic status.

SGLT2i in the inpatient management of acute decompensated heart failure (ADHF) continues to be an area of growing clinical interest. While clinical data regarding SGLT2i use in cardiogenic shock is limited, many recent trials have explored safety and efficacy of starting SGLT2i during in patients hospitalized for HF. The EMPAG-HF study assessed the early start of empagliflozin 25 mg in hospitalized patients with ADHF and displayed improved diuresis and kidney function compared to standard therapy without compromising blood pressure (BP) [16]. The EMPULSE trial further reinforced inpatient use, showing that empagliflozin led to improvement of symptoms, physical limitations, and overall health status, as measured by the Kansas City Cardiomyopathy Questionnaire [17]. The EMPA-RESPONSE-AHF study exhibited reduced combined endpoints of worsening HF, rehospitalization, death within 60 days, and improved natriuretic peptide levels when patients were on empagliflozin [18]. Dapagliflozin similarly showed promise in this setting as it had favorable effects on symptom relief and decongestant in patients who were hospitalized with ADHF, regardless of ejection fraction or diabetes status [19].

These studies suggest that SGLT2i can be safely initiated and may be beneficial in the inpatient setting, including during episodes of ADHF. Importantly, across trials such as EMPAG-HF, EMPULSE, and EMPA-RESPONSE-AHF, there was no excess risk of hypotension, acute kidney injury, or other adverse events compared to placebo. Although endpoints like decongestion or diuresis were variably affected—such as in DELIVER, where natriuretic benefit was not significant—the safety profile supports initiation prior to discharge. This strategy ensures patients are started on guideline-directed medical therapy (GDMT) early in the disease course, avoiding the common practice of deferring initiation to outpatient follow-up, where opportunities may be missed.

Key Point: Clinical trials have demonstrated safety, and in some cases improved diuresis, in hospitalized patients with ADHF, suggesting the benefits of starting SGLT2i during a HF hospitalization.

SGLT2i provide significant clinical benefits beyond diabetes and HF management, including reduction of BP among those with HTN. Although clinical significance in comparison to first-line agents is yet to be determined, numerous clinical trials have demonstrated statistically significant reductions in BP with SGLT2i [20].

The EMPA REG-BP explored the effect of empagliflozin on BP in patients with T2DM and HTN. Daytime mean systolic and diastolic BP were significantly reduced from baseline using both 10 mg and 25 mg dosages of empagliflozin when compared to placebo [21]. Subsequent subgroup analysis of this cohort yielded data showcasing preservation of BP-reducing effects with lower renal function and similar BP reduction with concomitant use of other antihypertensive medications. Results from this trial suggested additional mechanisms of action of BP reduction by SGLT2i beyond glucosuria, such as osmotic diuresis, weight loss, and reduced arterial stiffness [22].

A post hoc analysis of the CREDENCE trial showcases additional benefits of canagliflozin on BP reduction in individuals with T2DM and CKD. A reduction in BP was noted among all participants, regardless of baseline average BP and concomitant antihypertensive use. Notably, initiation of canagliflozin reduced the need for additional BP-reducing agents [23]. Similarly, the DELIVER and DECLARE-TIMI 58 trials provide evidence of dapagliflozin having a significant effect on BP in those with T2DM and HF or atherosclerotic disease. Both trials presented data supporting dapagliflozin’s role in CV benefit [6, 14].

Overall, these major trials, in addition to numerous other studies and meta-analyses, provide evidence to conclude that SGLT2i may result in a modest reduction in systolic and diastolic BP readings regardless of baseline HTN status and concomitant antihypertensive use [20]. Additionally, the data from these studies support the known CV, renal, and glycemic benefits of SGLT2i. This evidence supports the potential inclusion of SGLT2i as adjuvant therapy in HTN management, but further studies are required to conclude on its overall clinical significance compared to first-line agents for BP control.

Key Point: Although the clinical significance has not been established, current evidence suggests that SGLT2i may result in a modest reduction in systolic and diastolic BP readings.

AF has not been studied as a primary outcome in major CV trials of SGLT2i. Although emerging evidence suggests that SGLT2i may help reduce AF and related arrhythmia outcomes, dedicated research is needed to further determine the relationship between the two.

One retrospective cohort study of patients with T2DM undergoing AF ablation found that SGLT2i use was linked to a significantly lower risk of AF recurrence as measured by the need for cardioversion, new class I or III antiarrhythmic drugs, or repeat ablation [24].

Several systematic reviews and meta-analyses report that SGLT2i are associated with a reduced risk of AF (across occurrence, recurrence, and AF-related events), particularly in patients with T2DM or HF. Some analyses suggest the effect may be greater in subgroups such as patients with HFrEF, male individuals, those taking dapagliflozin, or those followed for longer periods [25,26,27,28]. In a meta-analysis of patients with pre-existing AF, SGLT2i were associated with a reduced risk of HF hospitalizations. [29]. However, a separate meta-analysis of 46 randomized controlled trials found no significant effect on overall AF occurrence, even at a 1-year timepoint, highlighting inconsistencies in the evidence [30]. Importantly, this and other analyses were limited in that they utilized fixed-effects models. They also lacked individual patient-level data and highlighted inconsistencies in how AF events were recorded across included studies.

Together, these limitations highlight the need for prospective trials specifically designed to evaluate the impact of SGLT2i on AF-related outcomes.

Key Point: Although early evidence suggests that SGLT2i may one day play a role in the management of AF, more research is needed.

T2DM continues to be the leading cause of kidney disease, yet effective long-term pharmacological interventions to slow down CKD progression remain limited [31]. Early CV trials of SGLT2i suggest potential renal benefits, extending beyond glucose and CV control [32, 33]. The specific impact of SGLT2i on patients with CKD, regardless of the patient’s glycemic status, was solidified in large-scale clinical trials such as CREDENCE, DAPA-CKD, and EMPA-KIDNEY [34,35,36]. These trials demonstrated significant reductions in composite renal endpoints, including sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease (ESKD), and renal death [37]. Of note, these significant renal benefits were consistent among patients irrespective of their glycemic status.

Furthermore, the long-term effects of SGLT2i, specifically empagliflozin, in patients with CKD were evaluated in the post-trial follow-up sub-study of EMPA-KIDNEY to assess the extended benefits of empagliflozin after its discontinuation. The trial demonstrated that in a broad population of patients with CKD at risk for disease progression, empagliflozin sustained additional cardiorenal protection for up to 1 year after the medication was stopped [38].

Key Points: Large-scale clinical trials have shown that SGLT2i reduce rates of composite renal endpoints irrespective of glycemic status.