INTRODUCTION
Sodium-glucose cotransporter 2 (SGLT2), a potent glucose transporter, is known to be a critical receptor located in the proximal segment of the renal tubule. It was established as the target for a class of antidiabetic medications known as SGLT2 inhibitors (SGLT2i). Guided by the recommendations of the Food and Drug Administration, a series of cardiovascular outcome trials were initiated for this pharmacologic class. These trials have gained significant attention, particularly because of the remarkable cardiovascular benefits they have demonstrated in individuals with diabetes mellitus.
Recognizing that these cardiovascular advantages could not be solely attributed to their glucose-lowering properties, investigators expanded their research on SGLT2i to include both diabetic and nondiabetic patients. Such research showed improved heart failure (HF) outcomes among patients with HF and reduced ejection fraction (EF) (HFrEF), with an EF of less than 40%, as well as in those with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF)—characterized by an EF >40%.
It is noteworthy that these randomized controlled trials primarily included diabetic patients or a mixed cohort comprising both diabetic and nondiabetic subjects. There is paucity of such randomized trials investigating the HF outcomes exclusively in nondiabetic patients. Similarly, several existing meta-analyses on HF outcomes have incorporated patients with diabetes mellitus or a mixed group encompassing individuals with and without the condition. Although these studies have provided valuable insights into the cardiovascular consequences of SGLT2i, their focus on the nondiabetic patient subgroup has predominantly centered on the single composite outcome of worsening HF and cardiovascular death. To the best of our knowledge, there is a conspicuous absence of comprehensive studies that exclusively investigate the diverse HF outcomes of SGLT2i in the nondiabetic patient population. To bridge this critical knowledge gap and to gain a nuanced understanding of the advantages of SGLT2i in nondiabetic patients concerning HF outcomes, we undertook this systematic review and meta-analysis.
MATERIALS AND METHODS
We conducted this meta-analysis according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines (Fig. 1). The protocol was not registered in any of the platforms.
We searched the online databases MEDLINE (using PubMed) and ClinicalTrials.gov between January 2015 and May 2023 using the search terms: SGLT2 inhibitors and HF. Studies were included if they met all the following criteria: (1) randomized controlled design on humans; (2) use of SGLT2i; (3) population was patients with HF, irrespective of EF; (4) population was nondiabetic patients; and (5) HF outcomes were analyzed in nondiabetic patients. Online search results were reviewed for potential inclusion in the meta-analysis. The references of the identified studies were manually reviewed to identify any potential additional studies.
After identifying the relevant studies, the data relevant to our meta-analysis were extracted, including the name of the study, year published, study population, EF, number of patients included in the treatment and placebo groups, number of events in the treatment and placebo groups, and outcomes that were analyzed in nondiabetic patients. The revised (version 2 of the) Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for quality assessment of the randomized controlled trials. The risk of bias was graded as low risk, some concerns, or high risk.
Data were analyzed using the meta package in R software (version 4.0.4), with the inverse variance method. To evaluate the need for random effects, 2 measures of heterogeneity were calculated: Higgins and Thompson's Ӏ2 statistic and the heterogeneity variance τ2. If the P value for heterogeneity was <0.1, a random effects model was considered to be indicated. A calculated P value of <0.05 was considered significant evidence of a treatment difference.
RESULTS
The online data search resulted in 2550 articles. Using the PRISMA algorithm, incorporating our inclusion criteria, and excluding studies that did not meet these criteria, 4 studies were identified for inclusion in the meta-analysis (Fig. 1). According to the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), no major risk of bias was found in any of the 4 studies (Fig. 2). The outcomes, which were common to these 4 studies, were analyzed, including the composite of worsening HF (hospitalization for HF and urgent visit for HF) and cardiovascular death, and the individual outcomes of HF hospitalization, cardiovascular death, and all-cause mortality (Table 1). In the figures and results that follow, we analyze each of these outcomes.
Composite of Hospitalization for HF, Urgent Visit for HF, or Cardiovascular Death
All 4 studies included in the meta-analysis demonstrated a trend toward improvement in this composite outcome. A subanalysis of the DAPA-HF trial by Petrie et al investigated the role of dapagliflozin in HFrEF (EF< 40%) in relation to glycemic levels. According to this, 4744 patients were randomized, and 4742 completed the trial. Of these, 55% (2605) were nondiabetic, with 1298 in the treatment group and 1307 in the placebo group. The primary outcome of this study was the composite of the first episode of worsening HF and cardiovascular death. This study defined worsening HF as unplanned admission to the hospital for worsening HF or an urgent hospital visit requiring treatment with intravenous therapy for HF. For patients without diabetes, this primary composite outcome occurred in 171 of 1298 patients (13.2%) in the treatment (dapagliflozin) group and 231 of the 1307 patients (17.7%) in the placebo group, with a hazard ratio (HR) of 0.73 and 95% confidence interval (CI) of 0.60–0.88, as shown in Figure 3. In this subgroup of patients without diabetes, volume depletion (7.3% in the treatment group and 6.1% in the placebo group) and kidney adverse events (4.8% in the treatment and 6% in the placebo group) are some of the major side effects noted.
Anker et al conducted a subanalysis of the EMPEROR-Reduced trial, which investigated the role of empagliflozin in patients with HF based on their baseline diabetes status. Among the total 3730 patients enrolled in the EMPEROR-Reduced trial, at the time of enrollment, 1268 (34%) had prediabetes defined as hemoglobin A1c [HbA1c] 5.7%–6.4%, and 606 (16%) had normoglycemia defined as HbA1c <5.7%, whereas the remaining 1850 (50%) had diabetes defined as HbA1C >6.4. Patients in the prediabetes and normoglycemia groups were considered patients with no diabetes. The primary outcome was a composite of cardiovascular death and hospitalization for HF. It occurred in 161 of the 936 nondiabetic patients (17.2%) in the treatment (empagliflozin) group and 197 of the 938 nondiabetic patients (21.0%) in the placebo group, with an HR of 0.78 (95% CI, 0.64–0.97), as shown in Figure 3. The study also found that empagliflozin was not associated with an increased risk of hypoglycemia and did not lower HbA1C in the subgroups of prediabetes and normoglycemia.
The EMPEROR-Preserved trial investigated the role of SGLT2i empagliflozin in patients with preserved ejection fraction (EF > 40%). A subgroup analysis by Filippatos et al evaluated the effect of empagliflozin in patients with HFpEF in relation to their diabetes status. In a total of 3050 patients without diabetes, 1531 were in the treatment group and 1519 in the placebo group. One hundred seventy-six of 1531(11%) in the treatment group and 220 of 1519 (14.5%) in the placebo group had the primary outcome of hospitalization for HF or cardiovascular death, with an HR of 0.78 (95% CI, 0.64–0.95), as shown in Figure 3. There was no increased risk of hypoglycemia in patients without diabetes compared with placebo.
DELIVER is another trial that investigated the role of an SGLT2i (dapagliflozin) in patients with HF with preserved EF. A subanalysis of this trial by Inzucchi et al evaluated the effect of dapagliflozin based on baseline glycemic status. Of the 6263 patients studied, 1175 had normoglycemia, 1934 had prediabetes, and 3150 had type 2 diabetes. The primary end point analyzed was the composite of worsening HF events (unplanned hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. In the normoglycemia group, 76 of 591 (13%) and 96 of 584 (16%) events occurred in the treatment and placebo groups, respectively, with an HR of 0.77 (95% CI, 0.57–1.04). In the prediabetes group, 142 of 960 (15%) and 163 of 974 (17%) events occurred in the treatment and placebo groups, respectively, with an HR of 0.87 (95% CI, 0.69–1.08). Patients with normoglycemia and prediabetes are clubbed together for this meta-analysis into the no-diabetes group. Of them, the number of these primary composite outcome events were 218 of 1551 patients in the treatment group and 259 of 1558 patients in the placebo group, with an HR of 0.83 (95% CI, 0.69–0.99; Fig. 3).
From the 4 studies, there were 10,638 nondiabetic patients, with 5316 patients in the SGLT2i group and 5322 patients in the placebo group, all included in our meta-analysis. For the outcome of the composite of worsening HF (hospitalization for HF and urgent visit for HF) and cardiovascular death, there were 726 events (13.66%) in the SGLT2i group and 907 (17.04%) in the placebo group. There was an overall beneficial effect of SGLT2i with an HR of 0.78 (95% CI, 0.71–0.86) and a P value of <0.0001 (Fig. 3), indicating a benefit in using SGLT2i even for nondiabetic patients in reducing the risk of the composite of HF hospitalizations, urgent visits for HF, and cardiovascular death.
HF Hospitalizations
Individual outcomes, which were common in most of these trials, were also assessed in our meta-analysis. Hospitalization for HF is 1 such outcome and remains a major issue in patients with HF and is associated with an increased risk of cardiovascular mortality.
In the trial by Petrie et al, the outcome of hospitalization for HF among nondiabetic patients occurred in 93 of 1298 patients (7.3%) in the treatment group and 146 of 1307 patients (11.5%) in the placebo group (HR of 0.63 and 95% CI, 0.48–0.81; Fig. 4), showing the benefit of dapagliflozin in decreasing hospitalizations in nondiabetic patients with HF with reduced EF. The study by Anker et al (subanalysis of EMPEROR-reduced trial) showed that of the 936 nondiabetic patients with HFrEF in the treatment (empagliflozin) group, there were 167 events of first or recurrent hospitalizations for HF, compared with 216 events of 938 patients in the placebo group, with an HR of 0.76 (95% CI, 0.57–1.01), as shown in Figure 4. The study by Filippatos et al showed a positive effect of empagliflozin in decreasing HF hospitalizations in nondiabetic patients with HFpEF with 157 of 1531 events in the treatment group and 206 events of 1519 in the placebo group, with an HR of 0.74 (0.56–0.97), as shown in Figure 4. The study by Inzucchi et al showed benefits in both the normoglycemic group (47 events in 591 patients in the treatment group vs. 66 of 584 patients in the placebo group, HR of 0.69, 95% CI, 0.47–1.00) and the prediabetic group (87 events in 960 patients in the treatment group, compared with 117 events of 974 patients in the placebo group, HR of 0.74, 95% CI, 0.56–0.98). The normoglycemia and prediabetic populations are grouped together as nondiabetic.
Our meta-analysis combining all these studies demonstrates that SGLT2i significantly decreased HF hospitalizations in nondiabetic patients; the number of events in the SGLT2i group were 551 (10.36%) and in the placebo group were 751 (14.11%), with an HR of 0.71 (95% CI, 0.62–0.81) and P value of <0.0001 (Fig. 4).
Cardiovascular Death
Cardiovascular death was another outcome analyzed in these studies and investigated in our meta-analysis. In all of the 4 studies, this outcome was not statistically significant. In the study by Petrie et al, among the nondiabetics, cardiovascular death occurred in 106 of the 1298 patients in the treatment (dapagliflozin) group and in 125 of the 1307 patients in the placebo group (HR of 0.85, 95% CI, 0.66–1.10; Fig. 5), which is not a statistically significant difference. In the study by Anker et al, the same outcome occurred in 83 of 936 patients in the treatment (empagliflozin) group and in 89 of 938 patients in the placebo group (HR 0.92, 95% CI, 0.68–1.24; Fig. 5), which again is not statistically significant. In the trial by Filippatos et al, in the nondiabetic patients, cardiovascular death occurred in 99 of 1531 in the treatment (empagliflozin) group and 121 of 1519 in the placebo group (HR 0.82, 95 CI, 0.63–1.07; Fig. 5), which is also not showing a statistically significant benefit. The study by Inzucchi et al, among the patients with normoglycemia, showed the outcome of cardiovascular death in 42 of 591 patients in the treatment (dapagliflozin) group and 51 of 584 patients in the placebo group (HR 0.82, 95% CI, 0.54–1.23). The same study showed that in patients with prediabetes, 66 of 960 patients in the treatment group had this outcome and 66 of 974 patients in the placebo group (HR of 1.02, 95% CI, 0.72–1.43). This study again showed no statistically significant benefit in both normoglycemic and prediabetic groups against the outcome of cardiovascular death compared with placebo.
Combining all these studies and performing a meta-analysis, we found that SGLT2i showed a favorable effect in decreasing cardiovascular death in nondiabetic patients with HF, with 396 events (7.45%) in the SGLT2i group compared with 452 (8.49%) in the placebo group, with an HR of 0.88, 95% CI, 0.77–1.00; however, this favorable effect of SGLT2i was not statistically significant (P= 0.059; Fig. 5).
All-Cause Mortality
There was no significant benefit against all-cause mortality among the 3 studies that reported this outcome. The study by Petrie et al showed that in nondiabetic patients, death from any cause occurred in 113 of 1298 patients in the treatment group and 151 of 1307 patients in the placebo group (HR 0.88, 95% CI, 0.70–1.12), as shown in Figure 6. In the study by Filippatos et al, 188 of 1531 patients in the treatment group experienced death from any cause compared with 201 of 1519 (HR of 0.94, 95% CI, 0.77–1.15), as shown in Figure 6. The study by Inzucchi et al showed that all-cause death occurred in 81 of 591 patients in the treatment group among normoglycemic patients and 100 of 584 patients in the placebo group (HR of 0.80, 95% CI, 0.60–1.07). Among prediabetics, death from any cause occurred in 150 of 960 patients in the treatment group and 137 of 974 patients in the placebo group (HR of 1.14, 95% CI, 0.90–1.44).
Including the data from all these studies, our meta-analysis showed that in nondiabetics with HF, SGLT2i had a neutral effect on all-cause mortality, with 552 events (10.38%) in the SGLT2i group compared with 586 (11.01%) in the placebo group, with an HR of 0.95 (95% CI, 0.84–1.07) and a P value of 0.37 (Fig. 6).
DISCUSSION
Various cardiovascular outcome trials have shown that SGLT2i can improve HF outcomes across all HF phenotypes, irrespective of left ventricular function. Real-world studies on diabetic patients, such as the CVD-REAL study by Kosiborod et al and the CVD-REAL Nordic study, also showed reduced hospitalizations for HF and cardiovascular mortality. Considering the overwhelming evidence, the European Society of Cardiology has recommended using SGLT2i empagliflozin and dapagliflozin for patients with HFrEF, irrespective of diabetes status. Similarly, American College of Cardiology/American Heart Association (ACC/AHA) guidelines also recommend SGLT2i for patients to decrease hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes in symptomatic chronic HFrEF (Class of recommendation Ia) and patients with HFpEF (Class of recommendation 2a).
Surprisingly, SGLT2i have cardioprotective benefits, although the cardiac muscles are not known to have SGLT2 receptors. The exact mechanism(s) by which SGLT2i confer the benefit of improving HF outcomes is still being determined. Several theories have been proposed for this purpose. One known mechanism of action of SGLT2i is their glucosuric and natriuretic effect, which can result in increased diuresis and volume loss, which can decrease the congestion and the cardiac preload. SGLT2i may also improve cardiac function by their ketogenic action by inducing hepatic ketogenesis and reducing ketonuria. These ketones eventually act as a source of energy for the cardiac muscle and help improve cardiac function. In a failing heart, there is increased Na+/H+ exchanger activity in the cardiac muscle cells, resulting in increased intracellular Na. SGLT2i inhibit Na+/H+ exchanger activity, decreasing intracellular Na+ and restoring mitochondrial Ca2+ levels, which can reduce the incidence of ventricular arrhythmias and sudden cardiac death.
SGLT2i can increase cardiac autophagy, a catabolic process by which potentially dangerous cellular components are removed by lysosomes, a process which is impaired in patients with HF and diabetes mellitus. By increasing cardiac autophagy, SGLT2i might reduce the components that can induce oxidative stress and inflammation, thus improving cardiac function in HF. SGLTI2i are also postulated to have various effects on blood vessels, such as alleviating endothelial dysfunction, promoting vasodilation, promoting the viability of endothelial cells, and decreasing arterial stiffness, thus improving vascular cell function and exerting their cardioprotective effects. SGLT2i can block the generation of reactive oxidative species and decrease oxidative stress. They may also reverse cardiac remodeling as demonstrated in 1 study that showed that empagliflozin decreased left ventricular mass index in 6 months compared with placebo. Evidence also suggests that SGLT2i decrease the circulatory levels of leptin and increase adiponectin a cardioprotective adipokine.
These pleiotropic effects and multifaceted mechanisms of action are believed to be responsible for the cardioprotective effects of SGLT2i, which further translates to improvement in HF outcomes. As one may notice, these benefits are not due to their glucose-lowering properties, and this can explain why SGLT2i have such cardioprotective effects even in nondiabetic patients, as we have seen in our study.
Previous randomized controlled trials on cardiovascular outcomes with SGLT2i have mainly focused on diabetic patients, although some of them have included mixed group of patients (both diabetic and nondiabetic patients). Large-scale studies with SGLT2i exclusively on patients without diabetes mellitus are limited, and several existing meta-analyses that do focus on SGLT2i and cardiovascular outcomes in patients with HF usually include patients both with and without the condition. Because nondiabetic patients are usually included as a subanalysis in these meta-analyses, the outcome assessed has usually been the primary outcome of the composite of worsening HF and cardiovascular death.
Vaduganathan et al performed a comprehensive meta-analysis, and one of the outcomes assessed was the composite of first hospitalization for HF and cardiovascular death for patients with no diabetes and found a significant benefit in the SGLT2i group with an HR of 0.77 (95% CI, 0.70–0.85). The same study found similar benefits in diabetic patients for the same outcome with an HR of 0.77 (95% CI, 0.70–0.84). Another meta-analysis by Pandey et al had a subanalysis on patients with HF with no diabetes. It showed the beneficial effects of SGLT2i in reducing the composite outcome of worsening HF (HF hospitalization or urgent visit for HF) and cardiovascular death (HR of 0.76 and 95% CI, 0.68–0.86). A meta-analysis by Zannad et al included a subanalysis on patients with HFrEF and without diabetes, including EMPEROR-Reduced and DAPA-HF trials, and it also showed beneficial effects on the outcome of the composite of all (first and recurrent) hospitalizations for HF and cardiovascular death (HR of 0.75 with 95% CI, 0.68–0.84). Another study by Teo et al found that the risk ratio for the composite of cardiovascular deaths and HF hospitalization in nondiabetic patients with HF on SGLT2i was 0.78 (95% CI, 0.69–0.89; P < 0.001) as determined by the random effects model. This study showed a statistically insignificant change in N-terminal pro b-type natriuretic peptide (NT-proBNP) in this patient population. However, this study included only 2 trials in the meta-analysis and did not evaluate other HF outcomes that are discussed here.
Our meta-analysis differs from the above meta-analyses as follows: First, unlike most of the above meta-analyses, our study is exclusively on nondiabetic patients. Second, the meta-analyses mentioned above obtained their data from primary studies, such as EMPEROR-Reduced, DAPA-HF, EMPEROR-Preserved, and DELIVER. However, our meta-analysis specifically reviewed and gathered data from the subanalysis of these primary studies that have investigated HF outcomes based on glycemic levels at enrollment. Third, among the nondiabetic patient population, the other meta-analyses investigated only the primary composite outcome (of worsening HF and cardiovascular death). However, our meta-analysis not only evaluated this composite outcome but also included and analyzed other outcomes including hospitalizations for HF, cardiovascular death, and all-cause mortality in nondiabetic patients.
In the trials included in this meta-analysis, we noticed that the total number of the events both in the treatment and placebo groups under each respective outcome is more in the diabetic group of patients compared with the nondiabetics, confirming the known fact that the patients with diabetes have relatively more cardiovascular events. Our study on nondiabetic patients showed statistically significant results in the SGLT2i group on the primary composite outcome of worsening HF and cardiovascular death (P < 0.001; Fig. 3). Similar benefit is also demonstrated in other meta-analyses as mentioned above which investigated this composite outcome in nondiabetics. In addition, our study also showed statistically significant results in the individual outcome of hospitalizations for HF (P < 0.001) in nondiabetics (Fig. 4). The benefit seen in the composite outcome is primarily driven by the significant benefit seen in the individual outcome of hospitalizations for HF.
Our meta-analysis showed favorable results of SGLT2i in the nondiabetic patients in decreasing cardiovascular death (HR of 0.88 and 95% CI, 0.77–1.0), although the difference was not statistically significant (P = 0.059; Fig. 5). This contrasts the findings from meta-analyses focusing on diabetic patients and mixed group of patients where there was a significant benefit. The absence of statistical significance for this outcome in our study might be attributed to the relatively lower number of cardiovascular death events in the nondiabetic group compared with the diabetic cohort.
Furthermore, our analysis revealed no significant advantage in all-cause mortality among nondiabetic patients treated with SGLT2i, with an HR of 0.95 (95% CI, 0.84–1.07) and a P value of 0.37 (Fig. 6). This outcome differs from the results observed in meta-analyses focused on diabetic patients and mixed patient groups, where a clear benefit was evident. One plausible explanation for this discrepancy is the limited number of events related to all-cause mortality in the nondiabetic subgroup compared with the diabetic population. In addition, our analysis of all-cause mortality comprised only 3 trials, with 2 of them focusing on patients with HFpEF (Fig. 6). Notably, in the HFpEF population, there seems to be a similarity in all-cause hospitalizations between the SGLT2i and placebo groups, as observed in the EMPEROR-Preserved trial. This similarity might suggest the presence of other confounding factors contributing to noncardiovascular causes of death among nondiabetic individuals included in these trials.
Our meta-analysis has certain limitations. First, our meta-analysis included only 4 studies because these are the only studies that satisfied the inclusion criteria. Second, the entity of HFmrEF (EF of 41%–49%) was not identified separately in our study and patients in this group were grouped with HFpEF. This is because HFmrEF is not defined separately in the studies included in the meta-analysis and patients who fall under this group are included under HFpEF in these studies. Third, 2 of the studies included normoglycemia and prediabetics as separate groups based on the enrollment HBA1C level, which are combined as nondiabetics in these studies. This meta-analysis did not assess whether there was a difference in the benefits in 1 group compared with the other (normoglycemia vs. prediabetes). Fourth, our study showed decreased cardiovascular death with SGLT2i in patients with HF without diabetes; however, a similar benefit was not seen with all-cause mortality. We tried to analyze the causes contributing to this mismatch as mentioned above; however, the reasons are not entirely clear and are an avenue for future research.
There are several ongoing studies on SGLT2i. The trials investigating the efficacy of dapagliflozin in hospitalized patients with HF include the DICTATE-AHF trial (Efficacy and Safety of Dapagliflozin in Acute HF) and the DAPA ACT HF-TIMI 68 trial (Dapagliflozin and Effect on Cardiovascular Events in Acute HF–Thrombolysis in Myocardial Infarction 68) (Clinical Trials.gov Identifier: NCT04363697). Studies on patients with acute MI investigating the role of SGLT2i in decreasing HF hospitalizations and cardiovascular mortality include the EMPACT-MI (A Study to Test whether Empagliflozin Can Lower the Risk of HF and Death in People Who Had a Heart Attack) and the DAPA-MI (Dapagliflozin Effects on Cardiovascular Events in Patients with an Acute Heart Attack) (Clinical Trials.gov Identifier: NCT04564742). Although we are unable to find information on ongoing large-scale randomized controlled trials on SGLT2i, which are exclusively on nondiabetic patients with HF, we expect to find more information on their benefits in nondiabetic patients from the subgroup analysis from the above and many other ongoing trials.
CONCLUSIONS
This meta-analysis shows that in nondiabetic patients with HF, SGLT2i are beneficial for decreasing the outcome of the composite of worsening HF and cardiovascular death. They have a significant benefit in decreasing hospitalizations for HF and have a favorable response to the outcome of cardiovascular death. However, they may not improve all-cause mortality in this patient population.
ACKNOWLEDGMENTS
The author thank Mr. Richard L. Berg, MS., senior biostatistician, Marshfield Clinic Research Institute, who conducted the statistical analysis for this meta-analysis and Mr. David S. Puthoff, Ph.D., scientific research writer, Marshfield Clinic Research Institute, who helped with language correction of this article.
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