|Year : 2021 | Volume
| Issue : 3 | Page : 156-165
Efficacy and safety of sodium-glucose co-transporter 2 inhibitors in heart failure patients: A systematic review and meta-analysis of randomized controlled trials
Yu-Cheng Wang1, Ming-Hui Li1, Ying Yu2, Hui Shi1, Rui-Zhen Chen1
1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
2 Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai 200032, China
|Date of Submission||27-Feb-2021|
|Date of Acceptance||03-Jun-2021|
|Date of Web Publication||30-Sep-2021|
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032
Source of Support: None, Conflict of Interest: None
Background and Objectives: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) significantly reduce the risk of cardiovascular events in patients with type 2 diabetes mellitus (T2DM). However, the effectiveness of SGLT2is in heart failure (HF) treatment has not yet been established. The aim of this meta-analysis was to assess the efficacy and safety of SGLT2is in HF treatment by focusing on cardiovascular death (CVD), hospitalization for HF (HHF), and a composite of CVD and HHF. Methods: We searched literature sources in PubMed, EMBASE, and Cochrane Library up until December 20, 2020. Only randomized controlled trials were included in this meta-analysis. We compared the treatment and placebo groups in terms of their associated risks of CVD and HHF and their safety endpoints. The Cochrane tool for assessing risk of bias in randomized trials was applied. Results: The 10 selected studies included 17,043 HF patients and dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, and sotagliflozin as experimental arms. At least 4 included studies were with high quality. For CVD, HHF, and their composite, the pooled risk ratio estimates were 0.87 (95% confidence interval [CI], 0.78–0.96; P = 0.004), 0.70 (95% CI, 0.65–0.76; P < 0.001), and 0.76 (95% CI, 0.71–0.81; P < 0.001), respectively. The incidence of volume depletion, hypoglycemia events, fractures, acute renal injury, and urogenital tract infection was not significantly higher in the SGLT2i group than in the placebo group. Stratified analyses showed similar efficacy and safety results for HF patients with T2DM, those without T2DM, and those being treated with different types of SGLT2is. Conclusions: This meta-analysis demonstrated that various SGLT2is significantly decreased the risks of CVD and HHF in HF patients with and without T2DM. It also showed that clinical administration of SGLT2is was relatively safe in terms of the aforementioned risk factors. SGLT2is might embrace broader clinical application in future HF treatment.
Keywords: Heart failure; Sodium-glucose transporter 2 inhibitors; Treatment; Type 2 diabetes mellitus
|How to cite this article:|
Wang YC, Li MH, Yu Y, Shi H, Chen RZ. Efficacy and safety of sodium-glucose co-transporter 2 inhibitors in heart failure patients: A systematic review and meta-analysis of randomized controlled trials. Cardiol Plus 2021;6:156-65
|How to cite this URL:|
Wang YC, Li MH, Yu Y, Shi H, Chen RZ. Efficacy and safety of sodium-glucose co-transporter 2 inhibitors in heart failure patients: A systematic review and meta-analysis of randomized controlled trials. Cardiol Plus [serial online] 2021 [cited 2021 Nov 27];6:156-65. Available from: https://www.cardiologyplus.org/text.asp?2021/6/3/156/327238
Authors Yu-Cheng Wang and Ming-Hui Li contributed equally to this work.
| Introduction|| |
Heart failure (HF) is a worldwide disease and is predicted that more than 8 million adults will be affected by HF by 2030. Novel approaches, such as angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, sacubitril/valsartan, and cardiac resynchronization therapies are being used to treat HF., Nevertheless, the prognosis of HF remains poor. Cardiovascular death (CVD) and hospitalization for HF (HHF) are severe outcomes of HF that require innovative and efficacious drug therapy. Type 2 diabetes mellitus (T2DM) and heart failure (HF) are often comorbid, and one disease independently increases the occurrence risk of the other. Elevated blood glucose-induced angiopathy, cardiomyopathy, and abnormality in energy metabolism, are the main causes of various diabetic cardiovascular complications. Recently, the antidiabetic agents – sodium-glucose co-transporter 2 inhibitors (SGLT2is) – have emerged as potential drug therapies for HF. Several large randomized controlled trials (RCTs) enrolling T2DM patients have demonstrated that SGLT2is lower the risk of cardiovascular events. The EMPA-REG OUTCOME, CANVAS program, and DECLARE-TIMI 58, showed that empagliflozin, canagliflozin, and dapagliflozin reduced the risk ratio (RR) of hospitalization for HF (HHF) by 35%, 33%, and 27%, respectively, compared with the placebo group.
It is also believed that SGLT2is can benefit patients with established HF patients. The major HF-specific RCTs, including DAPA-HF, EMPEROR-Reduced, and SOLOIST-WHF, revealed that dapagliflozin, empagliflozin, and sotagliflozin significantly reduced the risks of worsening HF events and cardiovascular death (CVD).,, Similar results were obtained for patients with and without T2DM., Hence, SGLT2is might effectively treat HF independently of blood sugar control. The newly updated CCS/CHFS HF guidelines strongly recommended SGLT2i administration to patients with mild-to-moderate HF with reduced ejection fraction (HFrEF) and concomitant T2DM. The CCS/CHFS HF guidelines also conditionally recommend the administration of SGLT2is to patients with mild-to-moderate HFrEF but no concomitant T2DM.
Although the EMPEROR-Reduced trial showed that empagliflozin reduced the risks of CVD and HHF, the 95% confidence interval (CI) for the CVD hazard ratio was 0.92 (range: 0.75–1.12), and it was not statistically significant. Another prospective observational pilot study recruiting 15 participants reported that empagliflozin did not improve peak VO2 in HF patients. Considering the small sample sizes of the qualified studies, it was necessary to conduct a data pooling analysis. There may have also been safety concerns about SGLT2is from the onset of the clinical trials on HF patients. These included volume depletion, hypoglycemia events, fractures, acute renal injury, urogenital tract infection, and amputation. To establish the therapeutic roles of SGLT2is in HF treatment, its efficacy and safety must be investigated in HF patients with various baseline diabetic characteristics. Moreover, the therapeutic roles of various types of SGLT2i types must be determined. In this meta-analysis of RCTs, we aimed to evaluate the efficacy and safety of different SGLT2is in HF treatment. We will include as much studies and HF patients as possible to determine the therapeutic role of SGLT2is in terms of HF disease and hope to provide more evidence in future clinical practices.
| Methods|| |
A systematic literature search was conducted by consulting the PubMed, EMBASE, and Cochrane Library databases up to December 20, 2020. Specific keywords were used, and there were no restrictions in terms of publication date, language, or article type. For example, the following terms were used for the first theme: canagliflozin OR dapagliflozin OR empagliflozin OR ertugliflozin OR ipragliflozin OR luseogliflozin OR tofogliflozin OR sotagliflozin OR SGLT-2 inhibitor. The following terms were used for the second theme: heart failure OR cardiac failure OR myocardial failure OR heart decompensation in PubMed. These terms were “All Fields” retrieval to avoid omitting any suitable studies.
Two independent reviewers identified articles for subsequent full-text review by screening abstracts and titles. The reviewers then read the full text of the conditionally selected articles to determine whether they should be included in this meta-analysis. Consensus on the retention of each article had to be reached. A third reviewer participated in the discussion and arbitration as required.
Eligible studies were RCTs with any of the SGLT2is as the intervention group, placebo as the control, and CVD, HHF, or their composite as the outcome. Subjects included in qualified studies presented with HF at the baseline with or without T2DM. Only studies published in the English language were included in this meta-analysis.
Bias risk assessment of the selected studies
Consensus was reached among independent investigators and bias risk assessments were conducted on all selected studies using the Cochrane tool for assessing risk of bias in randomized trials. The following aspects of each study were analyzed: random sequence generation, allocation concealment, blinding of patients and staff, blinding of outcome assessors and data analysts, lack of completion of outcome data, and selective reporting. For each domain, the bias risk was scored as low, high, or unclear. Two authors independently assessed each trial. Any discrepancy was resolved by discussion and consensus.
Two independent investigators used a predefined data extraction sheet to collect information from the selected studies. The items included authors, publication year, study design, population, sample size, country, follow-up months, number of subjects, ages, sex, and endpoint data in each group. Efficacy was the composite endpoint for CVD and HHF, CVD, and HHF. Volume depletion, hypoglycemia events, fractures, acute renal injury, urogenital tract infection, and amputation were the safety assessment endpoints. Endpoint data were separately collected based on the absence or presence of T2DM comorbidity. A third reviewer independently verified the data to confirm their accuracy. Detailed information on the design of certain trials was sought using the protocols provided in the supplementary materials of the articles. Data from urgent visits for HF were integrated with those for HHF, because both outcomes are significant in disease progression and indicate worsening of HF.
The meta-analysis was performed using Stata v. 13 (StataCorp, College Station, TX, USA). Data were pooled across studies using the random-effects model embedded in the “metan” command in Stata. Forest plots displayed the weights, RR estimates, and corresponding 95% CIs for the targeted studies. Analyses were performed separately according to patient baseline T2DM comorbidity or intervention characteristics. I2 statistics were calculated to identify heterogeneity. In general, I2 values of 25%, 50%, and 75% indicated low, moderate, and high heterogeneity, respectively. Sensitivity analyses were conducted to determine whether individual studies affected the aggregate result. Publication bias was evaluated with a funnel plot and Egger's test. P < 0.05 was considered statistically significant.
| Results|| |
Literature search and article selection
The initial search retrieved 1787 articles. After the first title and abstract screening, we obtained 75 articles for full-text review. Of these, 65 were excluded for the following reasons: study design (n = 22), protocol (n = 8) and conference abstract with insufficient information (n = 17), duplicate trial (n = 16), or no English text (n = 2). Hence, 10 articles were finally included in this meta-analysis. The study selection process is summarized in a PRISMA flow diagram [Figure 1].
The 10 studies included in this meta-analysis comprised 17,043 participants. The DAPA-HF, EMPEROR-Reduced, SOLOIST-WHF, and DEFINE-HF trials recruited HF patients with and without T2DM. Other trials including DECLARE-TIMI 58, CANVAS, EMPA-REG, CREDENCE, and VERTIS CV initially included T2DM patients with and without HF at baseline. One study reanalyzed the original data from five RCTs on patients with HF. They were combined into a single study for the purpose of this meta-analysis. However, we separately assessed bias risk for each of the five RCTs. The details of the studies included are listed in [Table 1].,,,,,
|Table 1: Baseline characteristics of the studies included in the meta-analysis|
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Bias risk assessment
Among all the included RCTs, we scored “unclear” in all domains if study protocol was not found. No risk of random sequence generation or allocation concealment was identified in any study. Since DECLARE-TIMI 58, CANVAS, EMPA-REG, CREDENCE, and VERTIS CV initially included T2DM patients with and without HF at baseline, we scored other bias sources as “high risk” in these studies. The bias risk assessment results are shown in [Table S1].,,,, In conclusion, at least 4 included studies were high quality in this meta-analysis.
Risks of cardiovascular and safety outcomes in the sodium-glucose co-transporter 2 inhibitor group compared with placebo in heart failure patients with or without type 2 diabetes mellitus comorbidity
To evaluate SGLT2i efficacy in HF patients, we pooled the data for the composite endpoints of CVD and HHF, CVD, and HHF, respectively, from 10 studies. For the CVD and HHF composite, the pooled RR was 0.76 (95% CI, 0.71–0.81; P < 0.001; I2 = 17.3%). Hence, there was a significant 24% risk reduction in the CVD and HHF composite events [Figure 2]A. The funnel plot revealed no publication bias [Figure S1]. For the Egger's test, P = 0.718. For CVD, the pooled RR estimate was 0.87 (95% CI, 0.78–0.96; P = 0.004; I2 < 0.1%). Thus, there was a significant 13% risk reduction in CVD [Figure 2]B. For HHF, the pooled RR was 0.70 (95% CI, 0.65–0.76; P ≤ 0.001; I2 = 3.7%). Therefore, there was a significant 30% risk reduction in HHF [Figure 2]C. From I2 results, these results showed low heterogeneity. All included studies except for one involving a CVD analysis showed an association between SGLT2i treatment and reduction of the risk of cardiovascular outcomes. However, the results were not statistically significant for all studies. The sensitivity analysis demonstrated that no individual study affected the aggregate results for these endpoints [Figure S2]A, [Figure S2]B, [Figure S2]C.
|Figure 2: Forest plot of cardiovascular outcomes in HF patients regardless of T2DM status to evaluate efficacy. SGLT2is significantly reduced the risks of the above three outcomes in HF patients regardless of T2DM. Low heterogeneity was shown in these results|
A, Composite of CVD and HHF. B CVD. C, HHF.
HF: Heart failure. T2DM: Type 2 diabetes, CVD: Cardiovascular death, HHF: Hospitalization for heart failure
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For HF patients with or without T2DM, SGLT2is did not significantly increase the risks of volume depletion (RR: 1.12 [0.99–1.26]; P = 0.062; I2 < 0.1%], hypoglycemia (RR: 1.08 [0.76–1.52]; P = 0.68; I2 < 0.1%), fracture (RR: 1.08 [0.88–1.34]; P = 0.466; I2 < 0.1%), acute kidney injury (RR: 0.77 [0.61–0.58]; P = 0.03; I2 = 34.8), or urogenital tract infection (RR: 1.27 [0.95–1.69]; P = 0.101; I2 = 34.3%). Nevertheless, SGLT2is significantly increased the risk of amputation (RR: 1.43 [1.01–2.03]; P = 0.046; I2 < 0.1%) [Figure S3]A, [Figure S3]B, [Figure S3]C, [Figure S3]D, [Figure S3]E, [Figure S3]F. No high heterogeneities were shown.
Risks of cardiovascular and safety outcomes in the sodium-glucose co-transporter 2 inhibitor group compared with placebo in heart failure patients with type 2 diabetes mellitus comorbidity
Nine studies included HF patients and T2DM. For CVD and HHF composite, the pooled RR was 0.75 (95% CI, 0.70–0.81; P < 0.001; I2 = 23%). Hence, there was a significant 25% risk reduction in CVD and HHF composite events [Figure 3]A. For CVD, the pooled RR estimate was 0.86 (95% CI, 0.77–0.96; P = 0.009; I2 < 0.1%). Thus, there was a significant 14% risk reduction in CVD [Figure 3]B. For HHF, the pooled RR was 0.70 (95% CI, 0.63–0.77; P ≤ 0.001; I2 = 22.5%). Therefore, there was a significant 30% risk reduction in HHF [Figure 3]C. These results also showed low heterogeneity in terms of the I2 results.
|Figure 3: Forest plot for cardiovascular outcomes in HF patients with T2DM to evaluate efficacy. SGLT2is significantly reduced the risks of the above three outcomes in HF patients with T2DM. Low heterogeneity was shown in these results|
A, Composite of CVD and HHF. B, CVD. C, HHF.
HF: Heart failure, T2DM: Type 2 diabetes, CVD: Cardiovascular death, HHF: Hospitalization for heart failure
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For HF patients with T2DM, SGLT2is did not significantly increase the risks of volume depletion (RR: 1.14 [0.98–1.33]; P = 0.078; I2 < 0.1%), hypoglycemia (RR: 1.12 [0.73–1.73]; P = 0.609; I2 < 0.1%), or fracture (RR: 1.00 [0.75–1.34]; P = 0.99; I2 = 21.5%). However, SGLT2is significantly increase the risk of amputation (RR: 1.45 [1.01–2.08]; P = 0.046; I2 < 0.1%) [Figure S4]A, [Figure S4]B, [Figure S4]C, [Figure S4]D. No high heterogeneities were shown.
Risks of cardiovascular and safety outcomes in the sodium-glucose co-transporter 2 inhibitor group compared with placebo in heart failure patients without type 2 diabetes mellitus comorbidity
The DAPA-HF and EMPEROR-Reduced trials recruited HF patients without T2DM. Therefore, we analyzed the safety outcomes and risks of cardiovascular manifestations in this population. For the CVD and HHF composite, the pooled RR was 0.77 (95% CI, 0.66–0.90; P = 0.001; I2 < 0.1%). Hence, there was a significant 23% risk reduction in CVD and HHF composite events [Figure 4]A. For CVD, the pooled RR estimate was 0.87 (95% CI, 0.70–1.09; P = 0.234; I2 < 0.1%) [Figure 4]B. For HHF, the pooled RR was 0.72 (95% CI, 0.55–0.93; P = 0.011; I2 = 42.3%). Thus, there was a significant 28% risk reduction in HHF [Figure 4]C. Low heterogeneity was shown in CVD and composite of CVD and HHF, while HHF outcome showed moderate heterogeneity.
|Figure 4: Forest plot for cardiovascular outcomes in heart failure patients without type 2 diabetes to evaluate efficacy. SGLT2is significantly reduced the risks of CVD and HHF composite and HHF in HF patients without T2DM. However, SGLT2is insignificantly reduced the risk of CVD in this group of patients. The first and second results showed low heterogeneity while the third outcome showed moderate heterogeneity|
A, Composite of CVD and HHF. B, CVD. C, HHF
T2DM: Type 2 diabetes, CVD: Cardiovascular death, HHF: Hospitalization for heart failure
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For HF patients without T2DM, SGLT2is did not significantly increase the risks of volume depletion (RR: 1.04 [0.82–1.33]; P = 0.743; I2 = 43.8%), amputation (RR: 0.52 [0.09–2.99]; P = 0.462; I2 < 0.1%), or fracture (RR: 1.27 [0.85–1.90]; P = 0.99; I2 < 0.1%) [Figure S5]A, [Figure S5]B, [Figure S5]C. No hypoglycemia events were reported for HF patients without T2DM regardless of SGLT2i or placebo intervention. No high heterogeneities were shown.
Effects of sodium-glucose co-transporter 2 inhibitor intervention compared with placebo on risks of cardiovascular outcomes
To evaluate the efficacy of various SGLT2is in HF patients, we analyzed the pooled cardiovascular outcomes according to SGLT2i type. In terms of the CVD, HHF, and composite endpoints, most of the SGLT2is demonstrated significant therapeutic efficacy. Nevertheless, canagliflozin did not significantly decrease CVD risk [Figure S6]A, [Figure S6]B, [Figure S6]C. The original and meta-analyzed results are summarized in [Table 2].
|Table 2: Risks of cardiovascular outcomes intervened by various sodium-glucose co-transporter 2 inhibitors|
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| Discussion|| |
The new SGLT2i antidiabetic drugs share a common mode of action and therapeutic effects. In this meta-analysis, 10 articles presenting 14 RCTs on dapagliflozin, canagliflozin, and empagliflozin were selected, and their data were extracted and analyzed. Compared with the placebo, SGLT2is lowered the risks of CVD, HHF, and their composite in HF patients with or without T2DM comorbidity. Moreover, SGLT2is did not significantly increase the risks of volume depletion, hypoglycemia events, fractures, acute renal injury, or urogenital tract infection relative to the control. However, SGLT2is did significantly increase the risk of amputation in HF patients presenting with T2DM comorbidity (P ≈ 0.05). However, since the incidence of amputation is relatively low and the statistical significance is close to the threshold, further larger investigation is required to establish whether the incidence of amputation is associated with SGLT2i administration. The mechanism of SGLT2i usage on amputation risk is still unclear; SGLT2i-induced hypovolemia and hypoperfusion might play a pathological role. Dapagliflozin, empagliflozin, and canagliflozin all demonstrated therapeutic efficacy against HF. The foregoing results suggested that SGLT2i was relatively safe for HF patients with or without T2DM and could improve their prognosis.
The present meta-analysis focused mainly on the effects of SGLT2is administered for the treatment of HF in patients with T2DM comorbidity. Stratified analyses were also conducted to determine the efficacy of SGLT2is in HF patients with or without T2DM. The results were similar for all HF patients regardless of T2DM status. In HF treatment, SGLT2is might also have a mechanism of action that is not associated with blood sugar regulation. Several hypotheses were proposed. (1) SGLT2is may reduce preload and afterload, thereby improving ventricular loading conditions. SGLT2is act on the proximal tubule and induce glucosuria and natriuresis. Osmotic diuresis decreases body fluid volume and cardiac preload. SGLT2is also lower blood pressure and, therefore, cardiac afterload. One study showed that empagliflozin reduced the 24-h systolic, diastolic, and central blood pressure in individual T2DM patients. A possible explanation for this observation could be the fact that SGLT2is improve endothelial function and aortic stiffness., (2) SGLT2is might improve myocardial metabolism and bioenergetics. SGLT2is increase the production of the ketone body β-hydroxybutyrate, which may be an alternative myocardial energy source in T2DM patients., A study comprising an untargeted metabolomics strategy indicated that SGLT2i administration promoted branched-chain amino acid degradation, thereby generating another alternative fuel source for the failing heart. (3) SGLT2is could directly inhibit the expression of the Na+/H+ exchanger (NHE) one isoform. In animal models, empagliflozin inhibited NHE1 expression in cardiomyocytes. This mechanism lowered cytoplasmic sodium and calcium levels and raised mitochondrial calcium levels. However, the cardiovascular benefits of cardiomyocyte NHE inhibition are inconclusive because no SGLT2 receptors are expressed in the human heart. (4) SGLT2is may inhibit cardiac fibrosis. An in vitro analysis revealed that empagliflozin significantly attenuated human cardiac fibroblast activation that is normally promoted by transforming growth factor-beta 1 (TGF-β1) and cell-mediated extracellular matrix remodeling. Gene expression profiling methods showed that SGLT2is also downregulated the expression of several critical profibrotic markers, such as COLA1, ACTA2, CTGF, FN1, and MMP-2. (5) SGLT2is showed favorable effects on renal function. The CREDENCE trial recruited patients with diabetic kidney disease and demonstrated that canagliflozin intervention reduced the relative risk of the composite endpoint of end-stage kidney disease by 30% (HR: 0.70; 95% CI: 0.59–0.82). The occurrence of cardiorenal syndrome hinders adequate management of patients with established HF. Hence, the renal benefits of SGLT2is contribute to their ability to improve HF prognosis.
Certain controversial adverse effects have been reported for SGLT2is. In the CANVAS program, amputation occurred relatively more frequently in response to canagliflozin administration. In the CREDENCE trial, however, there was no significant increase in the relative risk of amputation following canagliflozin treatment. There was no explanation for this discrepancy. In the DAPA-HF trial, all major hypoglycemia or ketoacidosis events occurred in HF patients with T2DM. In the EMPEROR-Reduced trial, empagliflozin worsened the prognosis of renal function deterioration and composite renal outcomes. Therefore, further research is required to explain the discordant reports on the adverse effects of SGLT2is and determine whether they differ between T2DM and non-T2DM populations. For example, detailed subgroup analysis or data mining studies using large-scale original data should be implemented to explore the specific patient characteristics associated with safety events, besides diabetic comorbidity. Analysis of the safety data for HF patients with or without T2DM revealed no difference between populations in terms of the safety endpoint risk. However, there was a slightly and significantly higher risk of amputation risk in patients with HF and T2DM who were being administered SGLT2is.
There were several limitations to this review. (1) Many of the included trials were not explicitly designed to investigate the roles of SGLT2is in HF treatment. Moreover, CVD and HHF were merely the predetermined rather than the primary endpoints. (2) The designs of the included trials were heterogeneous. In the EMPA-REG OUTCOME trial, HF was diagnosed based on a questionnaire. However, the CANVAS program and DECLARE-TIMI 58 trials relied upon medical histories rather than detailed HF trials. (3) Further investigations on the administration of other SGLT2is, such as ipragliflozin, luseogliflozin, and tofogliflozin, for HF treatment are necessary to confirm whether the various SGLT2is differ in terms of efficacy and safety. Additional testing, intervened by canagliflozin, ertugliflozin, and sotagliflozin on HF patients without T2DM, is required to broaden the clinical application of SGLT2is for HF therapy. However, since this meta-analysis included a relatively large number of patients and studies, it is credible to prove that multiple SGLT2is are beneficial to tackle HF, and will inspire future research to explore more types of SGLT2is in HF treatment field and the detailed mechanisms.
| Conclusions|| |
This meta-analysis demonstrated that SGLT2is significantly reduced the risks of CVD, HHF, and their composite in HF patients with or without T2DM. Moreover, SGLT2is were relatively safe in clinical practice. They did not significantly increase the risks of volume depletion, hypoglycemia events, fractures, acute renal injury, or urogenital tract infection relative to the control. This meta-analysis furnishes evidence that SGLT2is could be safe and efficacious when they are clinically administered for the treatment of HF patients with or without T2DM comorbidity. The cardiovascular benefits of SGLT2is indicate that they should be continuously administered to HF patients regardless of their glycemic status. Hence, SGLT2is might serve as both glucose-lowering therapeutic agents and novel treatments for HF. Although not all controversies are eliminated, SGLT2is might embrace broader clinical application in future HF treatment.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China (Grants No. 81772109, 81970315, and 81521001).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]