Effects of SGLT2 inhibitors on acute myocardial infarction: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-4901338/v1

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Effects of SGLT2 inhibitors on acute myocardial infarction: A systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-4901338/v1

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Background: Current treatment guidelines and expert consensus are controversial regarding the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) during acute progression of acute myocardial infarction (AMI) .Therefore, we conducted a systematic review and meta-analysis to evaluate the impact of SGLT2i on AMI , and safety outcomes in patients.

Methods: PubMed, Web of Science, Embase, China Science and Technology Journal Database, Wan fang Database and China National Knowledge Infrastructure Database were searched for clinical trials from database establishment to December 31，2023 with no language restrictions. The risk of bias was evaluated by Collaboration Handbook. Review Manager (version 5.3) were used for meta-analysis.

Results: A total of nine articles including 16083 patients were included. In patients with AMI, SGLT2i reduced the risk of the cardiovascular-death (RR 0.64, 95% CI 0.53–0.78, P<0.0001, I²=32% for the heterogeneity), hospitalization rate for heart failure (RR 0.69, 95% CI 0.53–0.90, P=0.006), arrhythmia (RR 0.53, 95% CI 0.33–0.86, P=0.009).

No significant differences were observed between the two groups with regard to all-cause deaths(RR 0.72, 95% CI 0.51–1.01, P=0.06), recurrence rate of myocardial infarction(RR 0.94, 95% CI 0.80–1.10, P=0.43), unplanned revascularization rate(RR 1.10, 95% CI 0.74–1.65, P=0.63)，and with similar risks of adverse events(RR 0.61, 95% CI 0.32–1.16, P=0.13)( such as acute kidney injury was lower than that of control group, genital infection was higher than that of control group).

Conclusions: This meta-analysis of patients with AMI showed that SGLT2i significantly reduce the risk of cardiovascular death , hospitalization and arrhythmia for AMI, but not recurrence rate of myocardial infarction, unplanned revascularization rate and all-cause death. Therefore, given that SGLT2i may reduce the risk of hospitalization and cardiovascular death for AMI, they should be considered the fundamental treatment for all patients with AMI.

sodium-glucose cotransporter 2 inhibitors

acute myocardial infarction

meta-analysis

Acute Myocardial Infarction (AMI) is a condition of severe myocardial ischemia and necrosis caused by acute narrowing or occlusion of the coronary arteries[1]. The global burden of AMI is growing, and has shown a younger trend, with approximately 50 deaths attributed to this condition every 100,000, and the number of AMI patients in China is expected to reach 23 million by 2030[2, 3]. Recently, reperfusion therapy is the main way of cardiac revascularization in AMI, but subsequent heart failure is the main cause of unplanned readmission and cardiac death in patients with myocardial infarction.

Sodium-GLucose cotransporter 2 inhibitors (SGLT2i) are a new class of oral hypoglycemic agents, and relevant studies have confirmed that they have a good cardioprotective effect[4–6], which can effectively improve the long-term prognosis of patients with heart failure. SGLT2i have been incorporated into the treatment of heart failure[7]. However, there is currently controversy over whether to use SGLT2i during acute progression of myocardial infarction[8], and it is unclear whether SGLT2i can reduce cardiovascular mortality and hospitalization rate of heart failure in patients[9, 10]. This study aimed to conduct a meta-analysis of clinical trials to determine the efficacy and safety of SGLT2i in patients with AMI.

Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [11], we performed a systematic review and meta-analysis to evaluate the effects of SGLT2i in patients with AMI. Through PubMed, Web of Science, Embase, China Science and Technology Journal Database, Wan fang Database and China National Knowledge Infrastructure Database of Clinical Trials, we searched for eligible clinical trials that explored the safety and efficacy of SGLT2i in individuals with AMI up to December 31, 2023. There were no criteria regarding publication time or language.

Inclusion and exclusion criteria

The inclusion criteria were as follows :(1) According to the diagnostic criteria of AMI; (2) Comparison of SGLT2i with placebo. reviews, case reports, reviews, Meta-analysis, letters, animal experiments, and non-SGLT2 inhibitor trials were excluded.

Outcomes of interest

The Primary outcome of interest included all-cause death, cardiovascular death, hospitalization rate for heart failure. Other cardiovascular outcomes of interest involved arrhythmia, Recurrence of myocardial infarction and unplanned revascularization. The parameters that were applied to evaluate the safety outcomes included any adverse event (AE), any serious AE, renal-related AE, acute kidney injury (AKI), volume depletion, hypoglycemia, urinary tract infection, thromboembolic event, genital infection.

Bias and quality assessment

The two researchers independently conducted an evaluation, preliminary selection, and literature verification using unified and standardized methods. They strictly adhered to the inclusion and exclusion criteria when selecting relevant literature for further analysis.

The quality of the selected articles was evaluated according to the Cochrane Reviewer Handbook 5.1.0 quality evaluation criteria (random sequence generation, allocation concealment, subject and personnel blinding, outcome evaluation blinding, incomplete outcome data, selective reporting, and other biases)[12].

Data extraction and quality assessment

The Review Manager (version 5.3) was used to record data and perform data analysis and quality assessment. Different variables were assigned different measures of effect, the risk ratio (RR) of the binary variable and the aggregate mean difference (MD) of the continuous variable. In addition, 95% confidence intervals (CI) were used for both variables. To measure the heterogeneity of the study, I² statistics were adopted. If the heterogeneity (I² > 50%, p < 0.05) is statistically significant, the random effect model is analyzed. Otherwise, select the fixed effect model. At the same time, subgroup analysis was performed to explore heterogeneity, and sensitivity analysis was performed to verify the robustness of the results. Finally, when no less than 10 studies were included in the analysis, funnel plots and Egger tests were used to assess publication bias.

Study selection and study characteristics

A total of 2920 studies were identified through the electronic searches, of which 274 were excluded due to duplication. 2578 studies were also excluded after reading the titles and abstracts. The remaining 59 studies were assessed by reading the full texts. Data from 9 clinical trials evaluating SGLT2i were included.

Nine[13–21] articles included were published from 2015 to 2023, A total of 16083 patients with a sample size ranging from 70 to 7000 were included in this meta-analysis. The process of study selection is depicted in Fig. 1. Dapagliflozin and empagliflozin were the main intervention measures. Meanwhile, the treatment duration of SGLT2i varied from 6 to 38 months. The detailed characteristics of this meta-analysis are presented in Table 1.

Table 1

The baseline characteristics of patients
	Region	Sample	Average age	Randomized Sectionalization	Baseline condition	Follow-up(month)	Effects	Adverse
Pasquale 2022	Italy	625	70 [61–79]	N	Comparable	24 ± 13	①②③④⑤	NR
Bernard 2015	Canada	7020	65	Y	Comparable	37.2	①②③④⑤	①②③④⑤⑥
Dirk 2022	Austria	476	57 (52–64)	Y	Comparable	6.5	①②⑤	②③⑤⑥
LiMing Xue 2021	China	70	56.26 ± 9.76	N	Comparable	12	②③⑤	NR
HaoZhang 2022	China	84	56.32 ± 12.19	Y	Comparable	3	②⑤	NR
Stefan 2023	Sweden	4017	62.8 ± 11.06	Y	Comparable	26	①②⑤	Y
Young Sang 2023	Korea	779	66.12 ± 10.86	N	Comparable	12	①②③④	NA
Osung Kwon 2023	Korea	2814	56.4 ± 11.3/57.6 ± 11.3	N	Comparable	25.2	①③⑤	NA
Ting-Yung 2022	Taiwan	198	66.1 ± 12.3/67.7 ± 11.9	N	Comparable	23.5 ± 15.7	②	NA
Outcome Indicator: ①All-cause deaths; ②Cardiovascular-deaths༛ ③Recurrence of acute myocardial infarction(Re-AMI)༛④Re-PCI༛⑤hospitalization rate for heart failure(HF Hospitalization)༛Security Index༚①Hypoglycemia༛②Urinary infection༛③Diabetic ketoacidosis༛④Event consistent with volume depletion༛⑤Acute renal failure༛⑥Event consistent with genital infection

The Primary outcome and other cardiovascular outcomes

SGLT2i significantly reduced the risk of the cardiovascular-death(RR 0.64, 95% CI 0.53–0.78, P < 0.0001, I² = 32% for the heterogeneity), hospitalization rate for heart failure (RR 0.69, 95% CI 0.53–0.90, P = 0.006), arrhythmia (RR 0.53, 95% CI 0.33–0.86, P = 0.009) (Fig. 2).No significant differences were observed between the two groups with regard to all-cause deaths(RR 0.72, 95% CI 0.51–1.01, P = 0.06), recurrence rate of myocardial infarction(RR 0.94, 95% CI 0.80–1.10, P = 0.43), unplanned revascularization rate(RR 1.10, 95% CI 0.74–1.65, P = 0.63) (Fig. 3).

Security analysis

The incidence of discontinuation due to adverse events did not significantly differ between the SGLT2i and placebo groups(RR 0.61, 95% CI 0.32–1.16, P = 0.13).In the overall cohort, the incidence of acute kidney injury (RR 0.73, 95% CI 0.60–0.87, P = 0.0007) was significantly higher in the SGLT2i; and genital infection was lower than that of SGLT2i group(RR 3.74, 95% CI 2.71–5.15, P < 0.00001).there were no statistically significant differences in the risk of volume depletion, hypoglycemia, urinary tract infection, thromboembolic event (Fig. 4).

AMI seriously damages health, with high morbidity and mortality[22]. Recently, the popularity of coronary intervention technology have enabled patients to receive timely and efficient treatment, but complications related with AMI have become the main factors of high mortality and high medical costs after successful revascularization[23, 24]. Therefore, reducing the complications related with AMI can effectively reduce the mortality and improve the prognosis of AMI.

This review comprehensively summarizes the evidence on the effects of SGLT2i on cardiovascular outcomes in patients with AMI. In a review of nine clinical trials, SGLT2i were found to be effective in reducing the risk of arrhythmia, Cardiovascular-death, and heart failure. In addition, the use of SGLT2i was similarly associated with all-cause mortality and myocardial infarction recurrence. In patients with AMI, no additional increase in total adverse effects was observed with SGLT2i compared with placebo, where the risk of kidney injury was lower than in the control group and the risk of genital infection was relatively higher.

In 2017, TM Lee[25] applied SGLT2i to rat ischemia-reperfusion models and found that SGLT2i could regulate the phenotype of macrophages in rats after infarction through RONS/Stat3-dependent pathways to reduce cardiac fibrosis and thus reduce myocardial infarction size in rats. Subsequently, the study was conducted using a pig model of myocardial ischemia, and it was found that SGLT2i could reduce oxidative stress response and increase the expression of mitochondrial antioxidant superoxide dismutase 2, thereby improving myocardial function and perfusion in ischemic areas, and thus improving the long-term prognosis of AMI. Subsequently, Liu[26] applied SGLT2i to preclinical models and clinical treatment analysis by analyzing pharmacological mechanisms of drugs, It was found that SGLT2i can improve the progression of atherosclerosis by inhibiting vascular inflammation, reducing oxidative stress, reversing endothelial dysfunction, reducing foam cell formation, preventing platelet activation and other mechanisms, thus reducing the occurrence of complications related with AMI ,and improving the prognosis of myocardial infarction. Therefore, the drug can be applied clinically. The results also confirmed that SGLT2i could reduce the risk of cardiovascular related death and the occurrence of heart failure in patients with AMI. The results of this study were consistent with that of this study, indicating that SGLT2i could effectively improve the prognosis of patients with AMI.

Our research sheds light on the safety considerations of SGLT2 in the treatment of AMI patients. In comparison to conventional treatment methods, our findings indicate that SGLT2i usage can effectively lower the risk of kidney injury. However, it is important to note that there is a relatively increased risk of genital infections associated with SGLT2i use. On the other hand, SGLT2i treatments demonstrate a relatively safe profile in terms of blood glucose levels, blood pressure, urinary tract infections, and diabetic ketoacidosis. It has been reported in the literature that SGLT2i have a significant renal protection effect on patients with diabetic nephropathy or non-diabetic nephropathy[27], which can reduce blood glucose and blood pressure levels by inhibiting the renal tubules' reabsorption of glucose and Na + and the over-activation of RAAS system[28].SGLT2i can also reduce proteinuria, inhibit the overactivation of sympathetic nerve, reduce oxidative stress and inflammatory response, and protect kidney function[29–31].After comparing the use of SGLT2i in 34,322 patients with type 2 diabetes, Zelniker[32] found that the incidence of heart failure was reduced and the progression of kidney disease was delayed, and found that SGLT2i could improve the kidney function of patients. Studies have also found that SGLT2i increase the risk of genital infection, and careful literature analysis has found that SGLT2i reduces the reabsorption of glucose /Na + into the proximal tubules, resulting in the formation of a continuously high urine glucose environment, and thus increases the risk of genital fungal infection[33].

However, there are some limitations to our study. First, there were differences in baseline characteristics such as age, type of reference, and duration of follow-up, which may have contributed to heterogeneity. Second, clinical trials of SGLT2i did not evaluate the validity of all relevant outcomes in patients with AMI, and even after contacting the authors of included trials, we were unable to obtain sufficient data to evaluate unreported outcomes or perform subgroup analyses. And due to the limited number of studies available, the strength of evidence for beneficial renal and cardiovascular outcomes in patients with AMI may not be well reflected .Finally, there are relatively few events where the use of different classes of SGLT2i and different treatment cycles could lead to certain safety outcomes.

Overall, the meta-analysis was able to demonstrate the cardiovascular benefits of SGLT2i in patients with AMI. In order to draw reliable conclusions about these efficacy outcomes, further larger trials are needed to evaluate the effect of SGLT2i in a sufficient number of patients with AMI.

In summary, the meta-analysis of AMI patients showed that SGLT2i significantly reduced the risk of arrhythmia, cardiovascular death, and hospitalization for heart failure, and improved kidney function without affecting changes in blood pressure and blood glucose in patients, with a good safety profile. Therefore, early addition of SGLT2i on the basis of standard treatment of AMI may become a trend in the treatment of myocardial infarction. However, due to the small number of included studies, more high-quality clinical trials are needed to verify this conclusion, so as to provide a more sufficient basis for SGLT2i to improve the prognosis of patients with AMI.

SGLT2i Sodium-GLucose coTransporter 2 inhibitors

AMI Acute myocardial infarction

AKI Acute kidney injury

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analysis

AE Adverse Event

MD Mean Difference

RR Risk Ratio

CI Confidence Intervals

Acknowledgements

Not applicable.

Authors’ contributions

The authors Chunmei Hu, Shulin Ou, Xi Zheng and Xianhua Tan were responsible for the conception and design of the study, acquisition of data, analysis and interpre tation of data, drafting the initial manuscript and revising it critically for impor tant intellectual content. The final draft was written by the authors Chunmei Hu, Shulin Ou. All the authors gave their approval to the final manuscript as it has been written.

Funding

No external source of funding or sponsorship was received for this study.

Availability of data and materials

Data is provided within the manuscript or supplementary information files.

Ethics approval and consent to participate

Ethical approval and consent to participate were not applicable to this systematic review and meta-analysis.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests

Author details

^1,2,3,4Department of Vasculocardiology, the peoples hospital of nanchuan , Affiliated Hospital of ChongQing Medical University, nanchuan,ChongQing 408400, China

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You are reading this latest preprint version

Effects of SGLT2 inhibitors on acute myocardial infarction: A systematic review and meta-analysis

Status:

Version 1

Abstract

Figures

Introduction

Methods

Inclusion and exclusion criteria

Outcomes of interest

Bias and quality assessment

Data extraction and quality assessment

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1