Abstract
Background:
Liraglutide widely utilized in type 2 diabetes treatment, has elicited conflicting findings regarding its impact on cardiac function in patients with this condition. Therefore, The objective of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of liraglutide on cardiac function in patients diagnosed with type 2 diabetes.
Methods:
We identified double-blind randomized trials assessing the effects of liraglutide compared to placebo on cardiac function in patients with type 2 diabetes. Data were synthesized with the fixed-effect models to generate standard mean differences (SMDs) with 95% confidence intervals (CIs) of each outcome for liraglutide versus placebo. The risk of bias would be assessed according to the Cochrane Risk of Bias Tool, while meta-analysis would be conducted using Revman 5.3.0 software. The evidence was graded based on the Grading of Recommendations Assessment, Development and Evaluation approach.
Results:
The meta-analysis encompassed 5 RCTs including 220 participants. Results revealed that liraglutide exhibited significant enhancements in left ventricular ejection fraction [SMD = −0.38, 95%CI(−0.70, −0.06), P = .02], cardiac index [SMD = −1.05, 95%CI(−1.52, −0.59), P < .0001], stroke volume [SMD = −0.67, 95%CI(−1.02, −0.32), P = .0002] and early diastolic filling velocity/late atrial filling velocity ratio [SMD = −0.52, 95%CI(−0.82, −0.22), P = .0006]. However, no statistically significant impact on cardiac output [SMD = −0.20, 95%CI(−0.53, 0.14), P = .26], early diastolic filling velocity/early diastolic annular velocity (E/Ea) ratio [SMD = −0.34, 95%CI(−0.75, 0.06), P = .10] and early diastolic filling velocity/early diastolic mitral annular velocity ratio [SMD = 0.21, 95%CI(−0.15, 0.56), P = .25] was observed. The Grading of Recommendations Assessment, Development and Evaluation evidence quality ratings indicated that all the outcome measures included in this study were evaluated as having low and very low quality.
Conclusion:
The available evidence suggested that liraglutide may exert a favorable impact on cardiac function in patients with type 2 diabetes. Consequently, the utilization of liraglutide as a preventive measure against heart failure incidents in individuals with type 2 diabetes represents a promising strategy. However, robust evidence support requires the conduct of large-scale, multicenter high-quality RCTs.
Keywords: cardiac function, liraglutide, meta-analysis, type 2 diabetes mellitus
1. Introduction
Diabetes has emerged as a pervasive global health crisis, with its prevalence exhibiting an alarming upward trend.[1] According to the World Health Organization, approximately 425 million individuals globally are affected by diabetes, with the majority being diagnosed with type 2 diabetes.[2] The pathogenesis of type 2 diabetes involves the coexistence of insulin resistance and inadequate insulin secretion, often accompanied by a constellation of metabolic disorders including hyperglycemia, insulin resistance, and insufficient insulin secretion.[3] In addition to the emphasis on glycemic control, individuals with diabetes are susceptible to numerous complications, among which cardiovascular disease stands out as one of the most prevalent and severe.[4] Cardiovascular disease is a leading cause of death in diabetic patients, and cardiac dysfunction represents a significant manifestation of this condition.[5] Studies have found that type 2 diabetes is associated with a 2 to 5-fold increased risk of heart failure, which in turn increases the risk of death in people with type 2 diabetes.[6] Diabetic cardiomyopathy is characterized by left ventricular diastolic dysfunction and may eventually progress to heart failure with ejection fraction preservation.[6,7] Therefore, it is imperative to identify a hypoglycemic agent capable of enhancing or safeguarding cardiac function in individuals with type 2 diabetes while lowering blood glucose.
Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, is a novel hypoglycemic agent for the treatment of type 2 diabetes.[8] GLP-1 is a multipotent metabolic endogenous incretin hormone that acts in the central nervous system to stimulate insulin release in a glucose-dependent manner, reducing glucagon levels and appetite, and thereby reducing blood glucose and body weight.[9,10] GLP-1 receptors are distributed in the gastrointestinal tract, cardiomyocytes, endothelial cells, and sinus node.[11,12] Therefore, liraglutide may exert cardioprotective effects by modulating cardiac function and preserving cardiomyocytes. Studies have demonstrated the efficacy of liraglutide in preventing and treating vascular complications of diabetes and alleviate myocardial damage.[13,14]
However, the impact of liraglutide on cardiac function in patients with type 2 diabetes remains uncertain. While certain studies have demonstrated the potential of liraglutide in enhancing indicators of cardiac function, others have yielded inconclusive results regarding any significant improvement. Therefore, a meta-analysis is necessary to comprehensively evaluate the effects of liraglutide on cardiac function in patients with type 2 diabetes and provide valuable references for clinical application.
2. Methods
The current systematic review and meta-analysis was performed and reported according to the items in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.[15]
2.1. Search strategy
A comprehensive search was carried out from PubMed, EMBASE, Web of Science, and Cochrane library to find randomized controlled trials (RCTs) assessing the effects of liraglutide compared to placebo on cardiac function in patients diagnosed with type 2 diabetes. The literature search was limited to studies published prior to December 31, 2023. The search strategy employed a combination of MeSH terms and free words. In addition, the retrieval process was conducted using a snowballing approach. Search terms were as follows: liraglutide, type 2 diabetes, randomized controlled trials, etc. Please refer to Table S1, Supplemental Digital Content, http://links.lww.com/MD/L842 for the retrieval strategy.
2.2. Inclusion and exclusion criteria
The selection criteria were based on the PICOS model.
Inclusion criteria:
Participants: Patients ≥ 18 years of age with diagnosis of type 2 diabetes;
Interventions: The intervention in the trial group were liraglutide treatment;
Comparison: The control group was treated with placebo;
Outcomes: ① Systolic cardiac function: left ventricular ejection fraction (LVEF), cardiac output, cardiac index and Stroke volume; ② Diastolic cardiac function: early diastolic filling velocity/early diastolic annular velocity (E/Ea), early diastolic filling velocity/late atrial filling velocity (E/A) and early diastolic filling velocity/early diastolic mitral annular velocity.
Study design: Only RCTs would be included in the study.
The exclusion criteria contained the following items:
Reviews, letters, case reports, or a summary of a meeting;
Experiments on animals;
Repeated publications.
2.3. Data extraction
The data were independently screened and extracted by 2 researchers according to the inclusion and exclusion criteria. The assistance of a third researcher would resolve any disagreement. To obtain the final literature in literature screening, first eliminate duplicates through the endnote, then read the title and abstract for initial screening, excluding those that did not meet the inclusion criteria, and further reading the full text of the literature.
Use Excel to extract literature data. Extract content: (1) basic information about the literature (title, first author, year of publication, type of study, registration number and country); (2) basic information about participants (age and sample size); (3) specific details of the intervention; (4) outcome indicators: systolic cardiac function and diastolic cardiac function. (5) Details of the risk of bias.
2.4. Quality assessment
The risk of bias were assessed according to the Cochrane Risk of Bias Tool.[16] Evaluation entries: ① method of allocation sequence generation; ② method of hiding allocation sequences; ③ double-blinding of performers and participants; ④ blinding in outcome assessment; ⑤ completeness of primary outcome data; ⑥ selective reporting; and ⑦ other sources of bias. The evaluation levels were categorized as “high risk,” “low risk,” and “unclear.”
2.5. Grading the quality of evidence
According to the Grading of Recommendations Assessment, Development and Evaluation (GRADE), the quality of evidence were independently evaluated and classified as high, moderate, low, or very low.[17]
2.6. Statistical analysis
The analysis was conducted using Revman 5.3.0 software. Standard mean differences (SMDs) and 95% confidence intervals (CI) were employed for continuous outcomes. Heterogeneity among studies was assessed using the χ2 test and I2 statistic. If there was no statistical heterogeneity in the results (P ≥ .1, I2 ≤ 50%), a fixed-effect model would be employed; however, if there was statistical heterogeneity present (P < .1, I2 > 50%), the random-effect model would be used. According to Tufanaru et al, fixed-effect models should be employed when the number of studies included in the meta-analysis was <5.[18]
3. Results
3.1. Basic characteristics of included studies
A total of 5[19–23] RCTs were included, with 107 in the liraglutide group and 113 in the placebo group(Fig. 1). All RCTs included were registered on an international trial registration platform. Two trials were conducted in the Netherlands and another 2 in Denmark. Furthermore, a separate study was carried out in Spain. The included sample size ranged from 24 to 60 cases. Placebo was used in all trials. The dose of liraglutide was 1.8mg. The follow-up period was 18 to 36 weeks. The basic characteristics of the included trials are shown in Table 1.
Figure 1.
Flow diagram of the study selection process.
Table 1.
Characteristics of included studies.
| Study, year | Country | Registration number | Participants | Ages | Intervention | Dose of Liraglutide | Follow up | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Treatment group | Control group | Treatment group | Control group | Treatment group | Control group | |||||
| Bizino et al (2019) | The netherlands | NCT01761318 | 23 | 26 | 60 ± 6 | 59 ± 7 | Liraglutide | Placebo | 1.8 mg | 26 weeks |
| Bojer et al (2019) | Denmark | NCT02655770 | 20 | 20 | 64 | 63 | Liraglutide | Placebo | 1.8 mg | 18 weeks |
| Kumarathurai et al (2021) | Denmark | NCT01595789 | 30 | 30 | 63.1 ± 6.6 | 63.1 ± 6.6 | Liraglutide | Placebo | 1.8 mg | 24 weeks |
| Paiman et al (2020) | The netherlands | NCT02660047 | 22 | 25 | 55 ± 11 | 55 ± 9 | Liraglutide | Placebo | 1.8 mg | 26 weeks |
| Wägner et al (2019) | Spain | 2012-005197-63 | 12 | 12 | 53.2 ± 9.7 | 52.6 ± 13.8 | Liraglutide | Placebo | 1.8 mg | 36 weeks |
3.2. Risk of bias in included studies
Five trials described methods for generating random sequences. Two trials assigned to hide showed low risk bias, and the rest were unclear. Other evaluation entries showed low risk bias. The results of risk bias are shown in Figure 2.
Figure 2.
Risk of bias summary.
3.3. Systolic cardiac function
3.3.1. Left ventricular ejection fraction.
Four trials were included: meta-analysis results indicated that liraglutide improved LVEF levels compared with placebo (SMD = −0.38, 95%CI(−0.70, −0.06), P = .02) (Fig. 3).
Figure 3.
Forest plot for the effect of liraglutide on left ventricular ejection fraction.
3.3.2. Cardiac output.
Three trials were included: meta-analysis results indicated no statistically significant difference in cardiac output between placebo and liraglutide (SMD = −0.20, 95%CI[−0.53, 0.14], P = .26) (Fig. 4).
Figure 4.
Forest plot for the effect of liraglutide on cardiac output.
3.3.3. Cardiac index.
Three trials were included: meta-analysis results showed that liraglutide improved cardiac index compared with placebo (SMD = −1.05, 95%CI(−1.52, −0.59), P < .0001) (Fig. 5).
Figure 5.
Forest plot for the effect of liraglutide on cardiac index.
3.3.4. Stroke volume.
Three trials were included: meta-analysis results showed that liraglutide improved stroke volume compared with placebo (SMD = −0.67, 95%CI(−1.02, −0.32), P = .0002) (Fig. 6).
Figure 6.
Forest plot for the effect of liraglutide on stroke volume.
3.4. Diastolic cardiac function
3.4.1. Early diastolic filling velocity/late atrial filling velocity.
Four trials were included: meta-analysis results showed that liraglutide improved E/A compared with placebo (SMD = −0.52, 95%CI(−0.82, −0.22), P = .0006) (Fig. 7).
Figure 7.
Forest plot for the effect of liraglutide on early diastolic filling velocity/late atrial filling velocity.
3.4.2. Early diastolic filling velocity/early diastolic annular velocity.
Two trials were included: meta-analysis results revealed no statistically significant difference in E/Ea between placebo and liraglutide (SMD = −0.34, 95%CI(−0.75, 0.06), P = .10) (Fig. 8).
Figure 8.
Forest plot for the effect of liraglutide on early diastolic filling velocity/early diastolic annular velocity.
3.4.3. Early diastolic filling velocity/early diastolic mitral annular velocity.
Three trials were included: meta-analysis results revealed no statistically significant difference in E/Ea between placebo and Liraglutide (SMD = 0.21, 95%CI(−0.15, 0.56), P = .25) (Fig. 9).
Figure 9.
Forest plot for the effect of liraglutide on early diastolic filling velocity/early diastolic mitral annular velocity.
3.5. GRADE evidence grading results
GRADE criteria were used to evaluate the quality of evidence for each outcome measures (Table 2). The GRADE classification indicated that the results of this study primarily relied on low-quality research, and further validation through larger sample sizes and higher-quality RCTs are needed in the future.
Table 2.
Summary of findings from the GRADE assessment.
| Outcomes | Risk of bias | Inconsistency | Indirectness | Imprecision | Publication Bias | Quality of evidence |
|---|---|---|---|---|---|---|
| Left ventricular ejection fraction | Serious limitations* | No serious limitations | No serious limitations | Serious limitations‡ | Serious limitations§ | Very low |
| Cardiac output | Serious limitations* | No serious limitations | No serious limitations | Serious limitations‡ | Serious limitations§ | Very low |
| Cardiac index | No serious limitations | Serious limitations† | No serious limitations | Serious limitations‡ | Serious limitations§ | Low |
| Stroke volume | Serious limitations* | Serious limitations† | No serious limitations | Serious limitations‡ | Serious limitations§ | Very low |
| Early diastolic filling velocity/late atrial filling velocity | Serious limitations* | No serious limitations | No serious limitations | Serious limitations‡ | Serious limitations§ | Low |
| Early diastolic filling velocity/early diastolic annular velocity | Serious limitations* | Serious limitations† | No serious limitations | Serious limitations‡ | Serious limitations§ | Very low |
| Early diastolic filling velocity/early diastolic mitral annular velocity | Serious limitations* | No serious limitations | No serious limitations | Serious limitations‡ | Serious limitations§ | Very low |
Certainty of evidence was downgraded by one level for risk of bias.
Certainty of evidence was downgraded by one level for heterogeneity.
Certainty of evidence was downgraded by one level for imprecision of results.
Certainty of evidence was downgraded by one level for publication bias.
4. Discussion
The meta-analysis included 5 RCTs with a total of 220 patients. Results demonstrated that liraglutide significantly improved LVEF, cardiac index, stroke volume and E/A ratio. However, no significant effects of liraglutide were observed on cardiac output, E/Ea ratio and E/e´ ratio. The findings suggested that liraglutide not only enhances systolic function to a certain degree, but also holds potential clinical benefits for ventricular diastolic function. Liraglutide effectively enhances cardiac systolic function, increase the amount of blood pumped per stroke, and improve ventricular diastolic function.
Although intensifying blood glucose control is the primary approach to reducing complications of diabetes, strict blood sugar control does not appear to improve diastolic function.[24] Liraglutide is an insulin sensitizer that has been widely used in the treatment of type 2 diabetes. Impaired left ventricular diastolic function is an early sign of diabetic cardiac damage, and early detection and intervention can reverse recovery in most patients.[25] Liraglutide, during its action process, can activate the signaling pathways within the patient’s body, reducing stress responses in myocardial cells and subsequently lowering the mortality rate of surrounding cells. This is beneficial for the recovery of left ventricular function.[26] The efficacy of liraglutide therapy in improving cardiac function indicators, including left ventricular systolic and diastolic functions, has been demonstrated by multiple studies.[27,28] The LEADER trial showed that liraglutide reduced total cardiovascular mortality in patients with type 2 diabetes and high cardiovascular risk.[29] These results suggested that liraglutide may improve quality of life in patients with type 2 diabetes by improving cardiac function. The findings of this meta-analysis hold significant implications for guiding clinical practice. Liraglutide has demonstrated efficacy in enhancing cardiac function among individuals diagnosed with type 2 diabetes, thus establishing itself as a pivotal therapeutic option. This advancement offers a more comprehensive range of treatment alternatives for individuals affected by diabetes, thereby mitigating the risk of cardiovascular disease and augmenting overall quality of life.
The efficacy of GLP-1 in improving cardiac function and treating chronic cardiac failure has been extensively validated by numerous studies.[30,31] Previous studies have suggested that the possible mechanisms of GLP-1 to improve cardiac function include inhibition of cardiomyocyte apoptosis, improvement of myocardial energy metabolism, increase of coronary blood flow, reduction of cardiac load, and enhancement of cardiac blood supply.[32,33] The GLP-1 receptor agonist liraglutide has been demonstrated to possess significant anti-inflammatory effects, while simultaneously reducing blood sugar level. Moreover, it exhibits the ability to inhibit atherosclerosis and improve myocardial injury and fibrosis through its anti-inflammatory properties, enhancement of oxidative stress, amelioration of endothelial dysfunction, inhibition of smooth muscle cell proliferation, anticoagulant activity, and plaque stabilization.[34,35] Consequently, this multifaceted mechanism contributes to the reduction in cardiovascular disease risk and mortality. Liraglutide has demonstrated natriuretic and vasodilatory effects, thereby attenuating the E/Ea ratio through modulation of cardiac preload.[36,37] In a double-blind randomized trial involving 33 diabetic patients, who were administered either liraglutide or placebo along with a 2-week exercise regimen, the liraglutide-treated group exhibited a significant reduction in the E/Ea ratio.[38] A meta-analysis conducted by Haroon et al[39] demonstrated that liraglutide significantly reduced the E/A ratio and E/Ea ratio in patients diagnosed with type 2 diabetes, indicating a potential clinical benefit on ventricular diastolic function. However, it did not exhibit any improvement in systolic function. Nevertheless, it is crucial to acknowledge that this meta-analysis included observational studies and further verification of these conclusions is required. In our study, which encompassed randomized controlled trials with double-blind placebo administration, we confirmed the potential benefits of liraglutide for ventricular diastolic function while also demonstrating an improvement in systolic function. Another meta-analysis conducted by Wang et al revealed favorable effects of liraglutide on blood glucose levels, cardiac function, lipid profiles, as well as its acceptable safety profile in patients diagnosed with type 2 diabetes combined with coronary artery disease.[40] Another meta-analysis indicated that liraglutide significantly improved cardiometabolic risk profile in patients with or without type 2 diabetes coronary artery disease.[41] In trials assessing cardiovascular outcomes, GLP-1 receptor agonist treatment reduced the risk of death from cardiovascular causes and fatal or nonfatal stroke in patients with type 2 diabetes compared to placebo, as revealed by a meta-analysis conducted by Qin et al[42] Currently, there is still controversy regarding the dosage of Liraglutide. Since the included RCTs in this meta-analysis recommended a dosage of 1.8mg, it was not possible to conduct comparative analysis between different dosages. However, based on current evidence and the results of this meta-analysis, a dosage of 1.8 mg for Liraglutide administration is both safe and effective. In the future, further exploration is needed to compare different dosages of liraglutide. In addition, the follow-up duration is crucial for evaluating the efficacy and safety of liraglutide in type 2 diabetes. This meta-analysis only included one study that assessed the long-term effects of liraglutide at 36 weeks. Therefore, further large-scale RCTs are needed to evaluate the long-term impact of liraglutide on patients with type 2 diabetes.
Several limitations exist in this study, including a limited sample size and a short follow-up duration, which may potentially impact the robustness of the findings. Therefore, cautious interpretation of our results is warranted. The protocol for this meta-analysis study was not registered on a public registry platform. Although we strictly adhered to the requirements stated in the PRISMA statement, there may still be potential biases present. The trials included in this study were conducted exclusively in patients from The Netherlands, Denmark, and Spain. Consequently, it is recommended to expand the sample sizes to encompass ethnically diverse populations within different ethnic contexts for further validation of our findings.
5. Conclusion
In summary, the results of the meta-analysis demonstrated that liraglutide exhibited significant enhancements in cardiac function among patients with type 2 diabetes. This finding presents a novel therapeutic approach and methodology for managing cardiac dysfunction in individuals with type 2 diabetes, thereby offering potential implications for clinical intervention. Future investigations should focus on expanding the sample size to enhance the evaluation of liraglutide’s efficacy in treating cardiac function among patients with type 2 diabetes.
Author contributions
Conceptualization: Wenjing Xia.
Data curation: Hua Yu.
Formal analysis: Wenjing Xia, Hua Yu.
Funding acquisition: Wenjing Xia.
Investigation: Hua Yu.
Methodology: Hua Yu.
Project administration: Wenjing Xia.
Resources: Hua Yu.
Software: Xia Lei.
Supervision: Wenjing Xia.
Validation: Xia Lei.
Visualization: Xia Lei.
Writing – original draft: Wenjing Xia, Pengcheng Wen.
Writing – review & editing: Wenjing Xia, Pengcheng Wen.
Supplementary Material
Abbreviation:
- CIs
- confidence intervals
- E/A
- early diastolic filling velocity/late atrial filling velocity
- E/e′
- early diastolic filling velocity/early diastolic mitral annular velocity
- E/Ea
- early diastolic filling velocity/early diastolic annular velocity
- GLP-1
- glucagon-like peptide-1
- GRADE
- Grading of Recommendations Assessment, Development and Evaluation
- LVEF
- left ventricular ejection fraction
- RCTs
- randomized controlled trials
- SMDs
- standard mean differences
Supplemental Digital Content is available for this article.
This work was supported by the Youth Science Foundation of Jiangxi province (20171BAB215029).
All analyses were based on previous published studies, thus no ethical approval and patient consent are required.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Xia W, Yu H, Lei X, Wen P. Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials. Medicine 2024;103:11(e37432).
Contributor Information
Hua Yu, Email: henlen.0111@163.com.
Xia Lei, Email: lx363648106@163.com.
Pengcheng Wen, Email: 13767252459@163.com.
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