The SGLT2i-mediated regulation of cardiovascular and safety outcomes among patients with chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials

doi:10.21203/rs.3.rs-2453557/v1

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The SGLT2i-mediated regulation of cardiovascular and safety outcomes among patients with chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials

https://doi.org/10.21203/rs.3.rs-2453557/v1

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Backgrounds: To assess the impact of SGLT2i on the cardiovascular and safety outcomes of patients with chronic kidney disease (CKD).

Methods: Eligible articles were chosen via a systematic search of the PubMed, Embase, and Cochrane electronic databases. We screened for randomized placebo-controlled clinical trials (RCTs) investigating the outcome of SGLT2i on patients with CKD. The main cardiovascular outcomes were major adverse cardiovascular events (MACE), which involved non-fatal myocardial infarction, non-fatal stroke and cardiovascular death, cardiovascular death and hospitalization for heart failure. On the other hand, acute renal injury, hypoglycemia, diabetic ketoacidosis, and amputation were considered as safety indicators for this trial. Renal insufficiency was defined as eGFR<90 mL per minute per 1.73m². In case the heterogeneity outcome index was ≥50%, we conducted sensitivity analysis on relevant data to ensure the reliability of our conclusions.

Results: Overall, 7 articles, involving 26739 total participants, conformed to our inclusion and exclusion criteria. Compared to placebo, SGLT2i significantly modulated cardiovascular outcomes MACE (OR: 0.76 95% CI: 0.68 to 0.86 I²:40.7% P: 0.168), cardiovascular death (OR: 0.83 95% CI: 0.72 to 0.95 I²26.4% P: 0.236), and hospitalization for heart failure (OR: 0.67 95% CI: 0.60 to 0.76 I²:0.0% P: 0.538), as well as safety outcomes, such as, acute renal injury (OR: 0.83 95% CI: 0.68 to 1.00 I²:0.0% P: 0.576), hypoglycemia (OR: 0.88 95% CI: 0.73 to 1.07 I²:18.4% P: 0.297), diabetes ketoacidosis (OR: 2.57 95% CI: 1.50 to 4.41 I²:46.3% P: 0.133), and amputation (OR: 1.09 95% CI: 0.87 to 1.36 I²; 0.0% P: 0.703).

Conclusion: In patients with CKD, SGLT2i usage markedly diminished incidences of cardiovascular outcomes MACE, cardiovascular death and hospitalization for heart failure. In addition, it also reduced the related risks of safety outcomes, such as, acute renal injury, hypoglycemia, diabetic ketoacidosis, and amputation. However, since the safety outcome selection was not complete in this trial, further investigations are necessary to assess all safety outcomes among a larger patient population.

SGLT2i

cardiovascular

safety outcomes

chronic kidney disease

At present, approximately 700 million people worldwide suffer from chronic kidney disease (CKD) [1], and over 3 million receive treatment. One study predicted that, by the year 2035, over 5 million CKD patients will receive treatment for this disease [2]. CKD has a gradual disease progression, and causes irreversible renal functional damage [3]. Moreover, with deteriorating function, multiple complications arise, such as, cardiovascular-related complications, which can increase patient mortality rate [4], and bring about enormous medical and economic challenges worldwide.

Prior investigations confirmed that SGLT2i not only reduces blood glucose, but also protects against cardiovascular events, and improves renal function [5], thus making it a highly efficacious and beneficial form of therapy [6–8].

The primary hypoglycemic mechanism of SGLT2i is to reduce the renal tubular reabsorption of glucose, minimize the renal threshold of glucose, and subsequently enhance the urine glucose excretion to ultimately lower blood glucose [9]. Although SGLT2i was originally developed to reduce blood glucose, it was later reported to enhance heart- and kidney-related outcomes in the clinic [10]. Till now, there is little information on the underlying mechanism behind the SGLT2i-mediated protection of the heart and kidney. It is entirely possible that these benefits may not be affected by the renal functional reduction and are independent of the hypoglycemic effect [11, 12]. Nevertheless, there are limited publications on the cardiovascular protection of SGLT2i among CKD patients. Several investigations revealed that following CKD3 (eGFR) of < 60 mL per minute per 1.73m², cardiovascular adverse events increase dramatically [13]. Therefore, it is of great clinical significance to examine the potential of SGLT2i in protecting against adverse cardiovascular and safety outcomes among CKD patients.

Emerging evidences validated that [3, 14, 15] SGLT2i minimizes cardiovascular events among CKD patients. However, the subjects included in these meta-analyses included renal insufficiency caused by diabetes, whereas, renal insufficiency brought on by other causes were not considered. Thus, herein, we performed a systematic review of patients with chronic renal insufficiency other than diabetes-induced nephropathy, regardless of the presence of absence of diabetes. Our goal was to collect more evidence to confirm the protective nature of SGL2Ti on the cardiovascular system among CKD patients.

Data sources and search strategies

The FFW, TTY, and CL systems in our team searched all clinical randomized controlled trials (RCTs) involving SGLT2i in the PubMed, Embase and Cochrane electronic databases in a standardized way, from the date of establishment of database till October 2022. The employed keywords words were as follows: “Sodium-Glucose Transporter 2 Inhibitors [Mesh]) OR Sodium Glucose Transporter 2 Inhibitors [Title/Abstract] OR (SGLT2inhibitors [Title/Abstract] and Renal Insufficiency [Title/Abstract]) OR (Kidney Insufficiency [Title/Abstract])) OR (Insufficiency, Kidney [Title/Abstract]))”. We also screened for significant conferences, reviews, and references in reviews for RCTs on SGLT2i. Once we selected the eligible articles, we conducted a secondary search to ensure accuracy of the article selection.

Research registration

This work is registered in the International Prospective Registry of Systematic Evaluation (PROSPERO, Registration No. CRD42022372153), and is reported according to the preferred reporting items of the systematic review and meta-analysis guidelines [16].

Study selection criteria

Inclusion criteria

1) Patients aged >30 years with renal insufficiency (eGFR<90 mL per minute per 1.73m²)

2) RCT examining SGLT2i

3) Study end point was the cardiac outcome index, and at least one safety index was acute renal injury or diabetic ketoacidosis or hypoglycemia or amputation

4) The study duration was not <24 weeks

Exclusion criteria

1) Non-RCT

2) Re-analysis from other tests or a pre-specified analysis of test results

3) End point outcome index involved no heart or acute kidney injury, diabetic ketoacidosis, hypoglycemia, or amputation

4) Animal Experimentation

Data extraction and quality assessment

The aforementioned FFW, TTY, and CL researchers extracted relevant information from the eligible articles. To conduct our analysis, we extracted the first author of each article, as well as the type of experiment, time of publication, follow-up time,the specific SGLT2i drugs used, and the drug meter. In terms of the study participants, we retrieved the patient number, age, glomerular filtration rate, and glycosylated hemoglobin. In terms of the outcomes of interest, we extracted MACE, cardiovascular death, and hospitalization for heart failure information. Lastly, we retrieved the safety outcome indicator data, such as, acute renal injury, hypoglycemia, diabetic ketoacidosis, and amputation. In case we encountered doubts or questions about the original text, relevant experts or literature were consulted, and, if necessary, the main person in charge of the trial was contacted to ensure accuracy of the extracted information.

Subsequently, we employed the Cochrane quality assessment tool [17] provided by the Review management version 5.4 to assess the bias risk of included articles. The bias risk was jointly completed by the FFW, TTY, and CL researchers. Lastly, in case of any differences in the statistical process, relevant professionals were consulted for proper resolution.

The study endpoints are listed below:

(1) MACE

(2) Cardiovascular death

(3) Re-hospitalization due to heart failure

In terms of safety outcomes, we selected acute renal injury, hypoglycemia, diabetic ketoacidosis, and amputation. All analyzed data were extracted from the selected articles, and were deemed to be true and reliable.

Data synthesis and analyses

Herein, we conducted a meta-analysis of the clinical and safety outcomes of SGLT2i usage among CKD patients.

We compared the exposure ratios (OR) with 95% confidence interval (CI). Inter-group heterogeneity determinations were made using the Chi (χ ²) and I square tests (Ι ²). We defined mild heterogeneity as ≤25%, moderate heterogeneity as 25-50%, and high heterogeneity as ≥50% [18]. If I²>50%, sensitivity analysis was employed. If I² was >50% following exclusion of relevant articles, the De Simone Laird random effect model was employed [19]. If I² ≤50%, the Mantel Haenszel fixed effect model was employed. All statistical analyses were performed using the STATA 17 software.

Patient and public participation

No patients or public participated in this trial, eliminating the need for ethical approval.

Research characteristics

Overall, 1564 relevant articles were identified from the Pubmed, Embase, and Cochrane electronic libraries. Following EndNote usage to screen for repeated articles, summary review to ensure fulfillment of the inclusion criteria, and screening of articles related to the outcomes of interest, only 42 articles were remaining. Finally, upon careful review of each article, 7 articles were included for analysis (Fig. 1), including, 2 articles involving dagelingin [1, 20], 2 articles involving sogliflozin [5, 21], 1 involving beshaggligin [22], 1 involving kagliflozin [2], and 1 involving engegligin [23]. In the included articles, the test group was administered SGL2Ti, and the control group was provided with placebo. All patients exhibited renal insufficiency, and several patients showed renal function (eGFR) of<30 mL per minute per 1.73m². In all, 26739 people participated in the 7 selected trials.(Table. 1)

Bias risk assessments and evidence

We next examined the quality of the selected 7 articles, and the bias risk assessment is provided in Fig. 2 and Fig. 3. All selected articles were clinical RCTs, and the reasons for trial termination, loss of certain subjects, and loss to follow-up were appropriately explained.

Influence of SGLT2i on MACE, cardiovascular death, and hospitalization for heart failure

Overall, there were 3235 cases of MACE, cardiovascular death, and hospitalization for heart failure within the 7 RCTs, including 1287 cases of MACE, 858 cases of cardiovascular death, and 1090 cases of hospitalization for heart failure. Using STATA17, a funnel chart was plotted for all outcomes (see supplementary materials Fig S1-S7), and potential publication bias was assessed. Based on our analysis, relative to placebo, SGLT2i markedly reduced incidences of MACE (Fig. 4), cardiovascular death (Fig. 5), and hospitalization for heart failure (Fig. 6) among CKD patients.

Influence of SGLT2i on acute renal injury, hypoglycemia, diabetic ketoacidosis, and amputation safety

Among the 7 RCTs, there were 1324 cases of acute renal injury, hypoglycemia, diabetes ketoacidosis, amputation and other safety outcomes. In particular, 671 cases occurred among the SGLT2i patients and 653 cases occurred among the controls. Based on these results, SGLT2i markedly reduced incidences of acute renal injury (Fig. 7), hypoglycemia (Fig. 8), diabetic ketoacidosis (Fig. 9), and amputation (Fig. 10), relative to controls.

Our meta-analysis of 7 RCTs provided evidence for the SGLT2i-mediated protection and safety against cardiovascular events among patients with renal insufficiency at various baselines. Based on our data, SGLT2i strongly reduced incidences of MACE, cardiovascular death, and hospitalization for heart failure.

Relative to controls, the SGLT2i also reduced the safety index, particularly, incidences of acute renal injury, hypoglycemia, diabetic ketoacidosis, and amputation. Given these evidences, SGLT2i application in preventing cardiovascular events among renal insufficiency patients has broad prospects and important clinical significance.

Previous demonstrations of the SGLT2i-based cardiovascular protective effect on patients with renal insufficiency was based on the analysis of pre-specified results or secondary analysis of prior trials. Till now, there has not been a meta-analysis to confirm that the included patients were from RCTs of renal insufficiency. Hence, this meta-analysis is the first comprehensive and systematic demonstration of this conclusion.

The underlying mechanism of the SGLT2i-mediated protection against cardiovascular events is not entirely clear. However, the potential cardiovascular mechanism can be understood from the following aspects. First, it is well established that the SGLT2i-induced improvements in cardiovascular recognized risk factors, namely, blood pressure, weight, uric acid, and proteinuria can be a contributing factor to enhancing the overall cardiovascular health. Second, the reduction of fluid overload and enhancement of natriuresis, caused by osmotic diuresis, as well as the reduction of arterial stiffness and improvement of vascular endothelial function, also critically modulate hemodynamic alterations to a certain extent. Third, SGLT2i directly acts upon the myocardium to reduce myocardial stretch, low-grade inflammation, and oxidative stress, as well as inhibit Na+– H + exchanger 1 (NHE1) activity, and enhance energetics due to using ketone as fuel. Fourth, SGLT2i may also positively modulate the endocrine system by increasing glucagon, decreasing the sympathetic tone, and enhancing the angiotensin converting enzyme angiotensin 1–7 pathway (ACE-ANG1-7) activity [24–27]. These aforementioned mechanisms involve the endocrine, circulatory, immune, and biochemical systems. They are not mutually exclusive of one another, however, they play their own roles. Since this is a hypothesis, there is no relevant test to prove its mechanism of action at the present time. Further basic test verification, special research, and confirmation are needed to elucidate and validate the mechanistic findings [28–32].

Apart from its role in reducing blood glucose, arterial blood pressure, and arteriosclerosis, SGLT2i also produces certain beneficial effects on the kidney, which can be understood from the following aspects. First, SGLT2i activates the intrarenal anti-inflammatory and anti-fibrosis pathways [33–35], improves renal oxygenation and mitochondrial function [36], and restores the tubular bulb feedback mechanism [28]. It also promotes the contraction of the small artery entering the glomerulus and the reduction of the intra glomerular hyperfiltration [20, 37, 38]. Second, since SGLT2i reduces blood glucose concentration, the kidney and other important organs are protected from glycotoxicity, which is conducive to reducing kidney growth, inflammation, and damage [31]. Third, SGLT2i also reduces the blood pressure, volume and weight of patients with renal insufficiency to a certain extent, which may, in turn, diminish the renal and cardiovascular burden [31, 39, 40]. Fourth, SGLT2 is generally co-expressed with the Na+/H + exchanger 3 (NHE3) membranal protein in the early proximal tubule, and it may accelerate natriuria, which may, in turn, have a positive effect on reducing blood pressure, thereby protecting the kidney [31]. Fifth, SGLT2i is related to glucagon levels, and glucagon partially contributes to maintaining renal function [31]. Glucagon dilates renal blood vessels, increases renal plasma flow, promotes glomerular filtration rate, and enhances electrolyte excretion. Other potential protective mechanisms include SGLT2 inhibitors which may reduce arterial stiffness and vascular resistance, lower uric acid level, and inhibit the angiotensin aldosterone system [41]. There may be more potential effects of SGLT2i on cardiovascular and kidney health, and further exploration of these potential mechanisms are necessary in patients with renal insufficiency.

In conclusion, for patients with renal insufficiency, SGLT2i significantly improves the incidence rate of cardiovascular disease, acute renal injury, hypoglycemia, diabetic ketoacidosis, and amputation. Regardless of whether a patient has diabetes or not, the SGLT2i-based mechanism of cardiovascular and kidney protection requires additional investigation and validation.

Advantages Of This Article

Herein, we present the first systematic review and meta-analysis on the cardiovascular protection and safety of SGLT2i among patients with chronic renal insufficiency. This investigation was conducted with strict standard research scheme and inclusion and exclusion criteria. In all, 7 RCTs were included for analysis, and these included a total of 26739 people. The selected RCT data were analyzed and the protective effect of SGLT2i on the cardiovascular system was evaluated. Our conclusions provided strong evidence for the cardiovascular protective effect of SGLT2i, as well as the effectiveness and safety of the drug SGLT2i.

Results Of Other Studies And Reviews

Although prior clinical trials supported the SGLT2i-mediated protection of the heart and kidney among patients with diabetic nephropathy or stage 3a/3b CKD, till date, there is no relevant meta-analysis on patients with non-diabetic nephropathy or renal insufficiency induced by other causes.

In all, 7 RCTs examining SGLT2i were included in our analysis. Among them, the CREDENCE trial consisted of patients with eGFR of 30–90 mL per minute per 1.73 m², accompanied with proteinuria of varying stages. The test conclusion was that among patients with type 2 diabetes and kidney disease, the renal failure and cardiovascular event risk among patients administered with cagelin was drastically lower than among patients administered with placebo [2]. This is consistent with the results of the cardioprotective effect of cagilegin in the CANVAS project [42]. Moreover, the EMPA-REG test confirmed that the heart protection experienced by the engegliptin group was better than the placebo group [43]. The famous DAPA-CKD test validated that the mortality risk due to kidney or cardiovascular causes among patients given daggliptin was significantly lower than patients given placebo [1]. This, together with the DECLARE – TIMI and DAPA-HF trials, support that SGLT2i substantially minimizes incidences of cardiovascular deaths and hospitalization for heart failure [9, 44]. In particular, diabetic ketoacidosis and hypoglycemia did not occur in the DAPA-CKD test. In terms of the trials involving bexagliflozin and sogliflozin, the safety and effectiveness of using bexagliflozin among CKD were the primary endpoints. Therefore, the indicators of interest were not kidney- and cardiovascular-related outcome indicators [21, 22]. Although these articles did not group cardiovascular basic diseases, patients with chronic heart failure and reduced ejection fraction were grouped in the meta-analysis of the DAPA-HF and empagliflozin outcome trials. Zannad et al. reported that SGLT2 inhibitors usage strongly diminished the risk of comprehensive outcome of hospitalization for heart failure or cardiovascular death among patients without diabetes by 25% [45]. In a systematic review and meta-analysis by Salah et al., SGLT2 inhibitors usage also strongly reduced the risk of hospitalization for heart failure by 48% [46].

At present, there are many clinical trials discussing the protective effect of SGLT2i on the cardiovascular system. However, the underlying mechanism is not completely clear. In the future, we warrant additional trials to elucidate the potential mechanism of SGLT2i on the cardiovascular system.

Limitations

This systematic review and meta-analysis has several limitations. First, although the glomerular filtration rate of all participants met the conditions of renal insufficiency, the baseline was different, which may have impacted the results. Second, part of the trial was short, and no long-term clinical follow-up was conducted Third, we did not consider the underlying cardiovascular diseases of the included patients, and perform subgroup analysis as appropriate.

This meta-analysis revealed that SGLT2i strongly reduces cardiovascular events among patients with renal insufficiency with basic diseases, and clinically proved its safety and effectiveness in the same group of patients.

Ethics approval and consent to participate

No patients or public participated in this trial, eliminating the need for ethical approval.

Consent for publication

Not Applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Competing interests

The authors declare that they have no conflict of interests.

Funding

National Natural Science Foundation of China 81874415

Authors' contributions

The FFW, TTY, and CL systems in our team searched all clinical randomized controlled trials (RCTs) involving SGLT2i in the PubMed, Embase and Cochrane electronic databases in a standardized way,and TTY had collected basic information of all patients who met the requirements.FRW provided ideas for the article and finally checked the article.YZ completed all the pictures and writed the whole article and checked all the data.

Acknowledgements

Not Applicable

Authors' information

Yi Zhou Doctor of Medicine Affiliated Hospital of Liaoning University of Traditional Chinese Medicine.Fengron wang Doctoral supervisor Affiliated Hospital of Liaoning University of Traditional Chinese Medicine.Feifei wen Doctor of Medicine Affiliated Hospital of Liaoning University of Traditional Chinese Medicine.

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Table 1 is available in the Supplementary Files section

No competing interests reported.

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The SGLT2i-mediated regulation of cardiovascular and safety outcomes among patients with chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials

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