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Effect of Glucagon-like Peptide-1 Receptor Agonists on Prognosis of Heart Failure and Cardiac Function: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Whether an antidiabetic drug, glucagon-like peptide-1 receptor agonist (GLP-1RA), could improve the prognosis of heart failure and cardiac function remains controversial. We conducted a systematic review and meta-analysis of randomized controlled trials to explore the influence of GLP-1RAs on heart failure in patients regardless of diabetes diagnosis.
Methods
Literature in English from the PubMed, EMBASE, and Cochrane Library databases was searched from inception to July 2022. The study aim was to identify published, randomized, placebo-controlled trials testing GLP-1RAs in patients with or without diabetes. Outcomes were heart failure hospitalization, cardiac function, and structure measures.
Findings
Twenty-two randomized controlled trials involving 61,412 patients are included in the meta-analysis. Overall, compared with the placebo group, GLP-1RA treatment could not significantly decrease heart failure hospitalization in patients with a history of heart failure (hazard ratio [HR], 1.07; 95% CI, 0.91 to 1.25; P = 0.422). Six-minute walking test distances (WMD, 19.08 m; 95% CI, 4.81 to 33.36; P = 0.01), E-wave (SMD, –0.40; 95% CI, –0.60 to –0.20; P < 0.001), early diastolic to late diastolic velocities ratio (WMD, –0.10; 95% CI, –0.18 to –0.02; P = 0.01), mitral inflow E velocity to tissue Doppler e′ ratio (WMD, –0.97; 95% CI, –1.54 to –0.41; P < 0.001), and E-wave deceleration time (WMD, –9.96 milliseconds; 95% CI, –18.52 to –1.41; P = 0.02) increased significantly after administration of GLP-1RAs. However, GLP-1RAs do not significantly influence N-terminal pro–B-type natriuretic peptide levels (WMD, –20.02 pg/mL; 95% CI, –53.12 to 13.08; P = 0.24), Minnesota Living with Heart Failure Questionnaire quality of life scores (WMD, –1.08; 95% CI, –3.99 to 1.84; P = 0.47), or left ventricular ejection fractions (WMD, –0.37%; 95% CI, –1.19 to 0.46; P = 0.38).
Implications
GLP-1RAs did not reduce heart failure readmissions in patients with a history of heart failure and elevated N-terminal pro–B-type natriuretic peptide levels. Thus, the prognosis of heart failure was not improved, although GLP-1RAs did significantly improve left ventricular diastolic function in patients. PROSPERO identifier: CRD42021226231.
It has been estimated that 23% of the population in developed countries suffers from heart failure. Reduced ventricular diastolic and systolic function not only are cardiac functional decompensation but also are important determinants of morbidity and long-term prognosis in the development of heart failure.
Thus, there is an urgent need to discover emerging therapies to improve cardiac function and heart failure prognosis.
Glucagon-like peptide-1 (GLP-1) is a hormone secreted by the small intestine that can reduce blood glucose by stimulating insulin production and inhibiting glucagon secretion.
GLP-1 receptor agonist (GLP-1RA) is a new hypoglycemic drug that has been recommended as first-line therapy for patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk or with established cardiovascular disease.
Precision medicine in diabetes: a Consensus Report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
The incidence of major cardiovascular events was significantly reduced in patients with T2DM treated with GLP-1RAs, suggesting that GLP-1–like molecules may have cardioprotective effects.
Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy.
Effects of oral antidiabetic drugs and glucagon-like peptide-1 receptor agonists on left ventricular diastolic function in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis.
Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. The Lancet.
However, these reports were conducted in patients with T2DM, and not all randomized controlled trials (RCTs) were included. Also, we identified new results assessing the impact of GLP-1RAs in patients, including N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, 6-minute walking test (6MWT) distance, and Minnesota Living with Heart Failure Questionnaire (MLHFQ) quality of life (QoL) score. The present study therefore evaluated the effect of GLP-1RA administration on the risk of heart failure hospitalization and the progress of heart failure and cardiac function in patients with or without T2DM using a meta-analysis of RCTs.
Materials and Methods
Protocol and Eligibility Criteria
We aimed to identify published, randomized, placebo-controlled trials testing GLP-1RAs. The research was based on the PICOS format: Whether taking GLP-1RAs (I) compared with placebo (C) has any effect on heart failure hospitalization, cardiac function, and structure measures (O) in adults who were either T2DM patients with or without cardiovascular disease or patients with cardiovascular disease alone, regardless of the use of dietary or exercise therapy (P). Trials meeting the following requirements were included: first, both injectable and oral agents were included, and the minimum intervention duration is 2 days. Second, the outcome of the included studies must contain the primary outcome (risk of heart failure hospitalization) or at least one of the following cardiac function and structure measures: left ventricular ejection fraction (LVEF), NT-proBNP, 6MWT, MLHFQ QoL score, E-wave velocity, A-wave velocity, early diastolic to late diastolic velocities ratio (E/A ratio), mitral inflow E velocity to tissue Doppler e′ ratio (E/e′ ratio), and E-wave deceleration time (EDT). This meta-analysis was prospectively registered in PROSPERO (CRD42021226231).
Information Sources and Search Strategy
Literature from the PubMed, EMBASE, and Cochrane Library databases was searched from inception to July 2022 according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
by using the following search terms: “glucagonlike peptide-1 receptor agonists,” “cardiac function,” “heart failure,” “lixisenatide,” “exenatide,” “liraglutide,” “semaglutide,” “albiglutide,” “dulaglutide,” “efpeglenatide,” “placebo,” and “randomized clinical trial.” The reference lists of the studies retrieved (including previous meta-analyses, systematic reviews, and review articles) were also searched for additional citations.
Data Extraction and Quality Assessment
Two independent reviewers were trained to screen titles and abstracts to determine whether they met the eligibility criteria. The reviewers read the full text and extracted relevant data after a consensus was reached. Any differences were resolved through discussion and arbitration, if necessary, by a third reviewer. The reasons for inclusion or exclusion were recorded in detail. Case reports, letters, and review articles were excluded. A total of 834 publications were identified, of which 22 studies (24 publications
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study.
Arteriosclerosis, Thrombosis, and Vascular Biology.2013; 33: 2252-2260
Effects of the novel long-acting GLP-1 agonist, albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction.
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial.
Effect of continuous exenatide infusion on cardiac function and peri-operative glucose control in patients undergoing cardiac surgery: a single-blind, randomized controlled trial.
Effect of liraglutide on cardiovascular function and myocardial tissue characteristics in type 2 diabetes patients of South Asian descent living in the Netherlands: a double-blind, randomized, placebo-controlled trial.
Journal of Magnetic Resonance Imaging.2020; 51: 1679-1688
Effect of once-weekly exenatide in patients with type 2 diabetes with and without heart failure and heart failure-related outcomes: insights from the EXSCEL Trial.
) were found eligible for the present meta-analysis (Table I, Figure 1). The Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram was used to summarize the study selection processes.
Table ISummary of trials evaluating the cardiac effects of glucagon-like peptide-1 (GLP-1) receptor agonists.
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study.
Arteriosclerosis, Thrombosis, and Vascular Biology.2013; 33: 2252-2260
Effects of the novel long-acting GLP-1 agonist, albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction.
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial.
Effect of continuous exenatide infusion on cardiac function and peri-operative glucose control in patients undergoing cardiac surgery: a single-blind, randomized controlled trial.
Effect of liraglutide on cardiovascular function and myocardial tissue characteristics in type 2 diabetes patients of South Asian descent living in the Netherlands: a double-blind, randomized, placebo-controlled trial.
Journal of Magnetic Resonance Imaging.2020; 51: 1679-1688
AMPLITUDE-O = Effect of Efpeglenatide on Cardiovascular Outcomes; ELIXA = Evaluation of Lixisenatide in Acute Coronary Syndrome; EXSCEL = Exenatide Study of Cardiovascular Event Lowering; FIGHT = Functional Impact of GLP-1 (Glucagon-Like Peptide-1) for Heart Failure Treatment; LEADER = Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; LIPER2 = Effect of Liraglutide on Physical Performance in Type 2 Diabetes; PIONEER 6 = Peptide Innovation for Early Diabetes Treatment 6; REWIND = Researching Cardiovascular Events with a Weekly Incretin in Diabetes; SUSTAIN-6 = Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes.
Two investigators used a predefined data extraction sheet to independently extract data from each included study (Table I). The third investigator independently reviewed the data to ensure accuracy. If an article presented more than one trial, data were extracted from each trial separately. The aforementioned data extraction process was repeated to avoid unnecessary errors.
Mean difference and corresponding SD of cardiac function and structure measures from baseline to the end of the intervention period were extracted from the experimental group and placebo group. SDs were often not available from the original publications but could be calculated from SEs of the mean and sample size, 95% CIs of estimated treatment differences, or from their reported interquartile ranges.
We calculated the mean difference by subtracting the end point from the baseline; the corresponding SD was calculated as √(SD2E baseline + SD2E final – 2 × R × SDE baseline × SDE final) referring to the “Cochrane Handbook for Systematic Reviews of Interventions.”
Quality Assessment
Based on the Cochrane “risk of bias” tool, quality assessment was measured through several aspects, such as random sequence generation and allocation concealment, description of dropouts and withdrawals, blinding (participants, personnel, and outcome assessment), the integrity of the results, selective outcome reporting, and other bias. All figures of quality assessment were made by using Review Manager 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark).
Meta-analysis
Depending on sample size, relevant hazard ratios (HRs), 95% CIs, mean change, and SD of the variation from both groups, the forest plots were drawn, presenting the overall estimates and heterogeneity values from each trial. Interstudy heterogeneity was assessed with the I² index and Cochran's Q test. We considered I² values lower than 25% to indicate low heterogeneity, values of 26% to 50% to indicate moderate heterogeneity, and values >50% to indicate high heterogeneity; Cochran's Q statistic P values below 0.05 were considered indicators for significant heterogeneity. When I² < 50% and P > 0.05, a fixed-effect model was taken. Once heterogeneity was found, two authors analyzed it by sensitivity analysis.
Publication Bias
Egger's tests were used to assess the publication bias in a quantitative method. If the P value was <0.05, publication bias was considered as existing. The trim-and-fill method was used to assess the stability of consolidation results when P < 0.05. All of the measures and graphs of publication bias were produced by using Stata 17.0 (StataCorp, College Station, TX, USA).
Results
Study Selection
Figure 1 displays the search procedures of this meta-analysis. A total of 834 articles were first identified from the PubMed, Cochrane Library, and EMBASE databases. After excluding 244 duplicates and 497 irrelevant articles, only 93 articles remained for the full-text review. Of these, 69 articles were further excluded according to the inclusion and exclusion criteria. As a result, 22 RCTs from 24 articles
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study.
Arteriosclerosis, Thrombosis, and Vascular Biology.2013; 33: 2252-2260
Effects of the novel long-acting GLP-1 agonist, albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction.
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial.
Effect of continuous exenatide infusion on cardiac function and peri-operative glucose control in patients undergoing cardiac surgery: a single-blind, randomized controlled trial.
Effect of liraglutide on cardiovascular function and myocardial tissue characteristics in type 2 diabetes patients of South Asian descent living in the Netherlands: a double-blind, randomized, placebo-controlled trial.
Journal of Magnetic Resonance Imaging.2020; 51: 1679-1688
Effect of once-weekly exenatide in patients with type 2 diabetes with and without heart failure and heart failure-related outcomes: insights from the EXSCEL Trial.
involving 61,412 participants were included in this meta-analysis.
Study Characteristics
As shown in the Table I, the intervention includes 8 drugs: lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide, efpeglenatide, and GLP-1 by injectable and oral agents. The follow-up duration of various GLP-1RAs ranged from 2 days to 5.4 years. Eleven studies reported heart failure hospitalization; 13 studies reported cardiac function and structure measures, including NT-proBNP levels, 6MWT, QoL, ventricular systolic function (LVEF), and diastolic function (E-wave, A-wave, E/A ratio, E/e′ ratio, and EDT). Participants in 19 trials were patients with T2DM, and participants in 15 studies were patients with a history of heart failure.
Risk of Bias Within Studies
According to the figure of bias risk, a few trials failed to clarify the potential bias, which was regarded as unclear status. Random sequence generation and allocation concealment were reported in RCTs. The blinding (participants, personnel, and outcome assessment), selective reporting, and the integrity of outcome data were rated as low bias among a large proportion of the trials (see Supplemental Figures 1 and 2).
Synthesis of Results
Effects of GLP-1Ras on Heart Failure Hospitalization
We identified a participant's first hospital admission for heart failure after taking GLP-1RAs during the follow-up period as heart failure hospitalization. The effects of GLP-1RA treatment on the whole risk of heart failure hospitalization were presented in 11 trials
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
enrolling 60,766 patients. The corresponding I2 values were 0%. Pooled results from the fixed effect model revealed that GLP-1RAs do significantly reduce the whole heart failure hospitalization (HR, 0.91; 95% CI, 0.84–0.99; P = 0.03) (Figure 2).
Figure 2Forest plot comparing the risk of heart failure hospitalization between the glucagon-like peptide-1 receptor agonist (GLP-1RA) groups and the placebo groups.
Effect of once-weekly exenatide in patients with type 2 diabetes with and without heart failure and heart failure-related outcomes: insights from the EXSCEL Trial.
GLP-1RAs significantly reduced the risk of heart failure hospitalization in patients with no history of heart failure (HR, 0.84; 95% CI, 0.71–1.00; P = 0.045). However, GLP-1RAs do not significantly influence heart failure rehospitalization in patients with a history of heart failure (HR, 1.07; 95% CI, 0.91–1.25; P = 0.422) (Figure 3). There was a significant difference between the 2 subgroups (P = 0.045).
Figure 3Forest plot for heart failure subgroup analysis. (A) With a history of heart failure. (B) With no history of heart failure. GLP-1RA = glucagon-like peptide-1 receptor agonist.
Effects of GLP-1RAs on NT-proBNP, the Distance of 6MWT, and MLHFQ QoL Score
Changes in NT-proBNP levels, the distance of 6MWT, and MLHFQ QoL score reflect cardiac function and prognosis of patients with heart failure. Lower NT-proBNP levels, higher 6MWT distances, and lower QoL scores indicate improved cardiac function. The effects of GLP-1RA treatment on NT-proBNP levels were presented in 5 trials
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
enrolling 707 patients. All corresponding I2 values were 0%. Pooled results from the fixed-effect model revealed that GLP-1RAs do not significantly influence plasma NT-proBNP levels (WMD, –20.02 pg/mL; 95% CI, –53.12 to 13.08; P = 0.24) (Figure 4).
Figure 4Forest plot comparing changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels (A), 6-minute walking test (6MWT) (B), and (C) quality of life (QoL) between the glucagon-like peptide-1 receptor agonist (GLP-1RA) groups and the placebo groups.
Effects of the novel long-acting GLP-1 agonist, albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction.
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
enrolling 711 patients. The corresponding I2 values all were 0%. Pooled results from the fixed-effect model revealed that GLP-1RAs significantly increase the distance of 6MWT (WMD, 19.08 m; 95% CI, 4.81–33.36; P = 0.01) (Figure 4).
The effects of GLP-1RA treatment on QoL score were presented in 3 trials
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
enrolling 562 patients. The corresponding I2 values all were 0%. Pooled results from the fixed-effect model revealed that GLP-1RAs do not significantly influence QoL score (WMD, –1.08; 95% CI, –3.99 to 1.84; P = 0.47) (Figure 4).
Effects of GLP-1RAs on Ventricular Systolic Function
LVEF is a valid index of left ventricular systolic function, thus reflecting the status of cardiac function. The stronger the myocardial contractility, the higher the LVEF. The effects of GLP-1RA treatment on LVEF were presented in 13 trials
Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study.
Arteriosclerosis, Thrombosis, and Vascular Biology.2013; 33: 2252-2260
Effects of the novel long-acting GLP-1 agonist, albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction.
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial.
Effect of continuous exenatide infusion on cardiac function and peri-operative glucose control in patients undergoing cardiac surgery: a single-blind, randomized controlled trial.
Effect of liraglutide on cardiovascular function and myocardial tissue characteristics in type 2 diabetes patients of South Asian descent living in the Netherlands: a double-blind, randomized, placebo-controlled trial.
Journal of Magnetic Resonance Imaging.2020; 51: 1679-1688
enrolling 1023 patients. The corresponding I2 values all were 0%. Pooled results from the fixed-effect model revealed that GLP-1RAs do not significantly influence LVEF (WMD, –0.37%; 95% CI, –1.19 to 0.46; P = 0.38) (Figure 5).
Figure 5Forest plot comparing changes in left ventricular ejection fraction between the glucagon-like peptide-1 receptor agonist (GLP-1RA) groups and the placebo groups.
Effects of GLP-1RAs on Ventricular Diastolic Function
Commonly used evaluation indexes of diastolic function include the mitral Doppler ultrasound indexes E/A ratio, E/e′ ratio, and EDT. The effects of GLP-1RA treatment on E waves were presented in 5 trials
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial.
Effect of liraglutide on cardiovascular function and myocardial tissue characteristics in type 2 diabetes patients of South Asian descent living in the Netherlands: a double-blind, randomized, placebo-controlled trial.
Journal of Magnetic Resonance Imaging.2020; 51: 1679-1688
enrolling 385 patients. The corresponding I2 values all were 39.77% (P = 0.16). Pooled results from the fixed-effect model revealed that GLP-1RAs significantly decrease the E wave (SMD, –0.40; 95% CI, –0.60 to –0.20; P < 0.001) (Figure 6). E wave refers to early peak left ventricular diastolic blood flow velocity.
Figure 6Forest plot comparing changes in the E wave (A), A wave (B), early diastolic to late diastolic velocities ratio (E/A ratio) (C), mitral inflow E velocity to tissue Doppler e′ ratio (E/e′ ratio) (D), and E-wave deceleration time (EDT) (E) between the glucagon-like peptide-1 receptor agonist (GLP-1RA) groups and the placebo groups.
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial.
Effect of liraglutide on cardiovascular function and myocardial tissue characteristics in type 2 diabetes patients of South Asian descent living in the Netherlands: a double-blind, randomized, placebo-controlled trial.
Journal of Magnetic Resonance Imaging.2020; 51: 1679-1688
enrolling 385 patients. The corresponding I2 values all were 0% (P = 0.92). Pooled results from the fixed-effect model revealed that GLP-1RAs do not significantly decrease A waves (SMD, 0.16; 95% CI, –0.04 to 0.36; P = 0.12) (Figure 6). A wave refers to late peak left ventricular diastolic flow velocity.
The effects of GLP-1RA treatment on the E/A ratio were presented in 5 trials
Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study.
Arteriosclerosis, Thrombosis, and Vascular Biology.2013; 33: 2252-2260
Effect of liraglutide on cardiovascular function and myocardial tissue characteristics in type 2 diabetes patients of South Asian descent living in the Netherlands: a double-blind, randomized, placebo-controlled trial.
Journal of Magnetic Resonance Imaging.2020; 51: 1679-1688
enrolling 268 patients. The corresponding I2 values all were 18.79% (P = 0.30). Pooled results from the fixed-effect model showed that GLP-1RAs significantly decrease the E/A ratio (WMD, –0.10; 95% CI, –0.18 to –0.02; P = 0.01) (Figure 6). The E/A ratio indicates the influence of atrial contraction on mitral valve flow and can be used to evaluate the diastolic function of the left ventricle. The E wave is greater than the A wave under normal conditions, but the E/A ratio is also >1 in mild and severe diastolic function impairment.
The effects of GLP-1RA treatment on the E/e′ ratio were presented in 6 trials
Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study.
Arteriosclerosis, Thrombosis, and Vascular Biology.2013; 33: 2252-2260
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial.
Effect of liraglutide on cardiovascular function and myocardial tissue characteristics in type 2 diabetes patients of South Asian descent living in the Netherlands: a double-blind, randomized, placebo-controlled trial.
Journal of Magnetic Resonance Imaging.2020; 51: 1679-1688
enrolling 459 patients. The corresponding I2 values all were 0% (P = 0.60). Pooled results from the fixed-effect model revealed that GLP-1RAs significantly decrease the E/e′ ratio (WMD, –0.97; 95% CI, –1.54 to –0.41; P < 0.001) (Figure 6). The E/e′ ratio is of great value in the evaluation of diastolic function and has high prediction accuracy. e′ is the early peak diastolic velocity at the root of the mitral annulus. The increase of the E/e′ ratio indicates the increase of left ventricular diastolic filling pressure and abnormal diastolic function. However, GLP-1RAs could reduce E/e′.
The effects of GLP-1RA treatment on EDT were presented in 5 trials
Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study.
Arteriosclerosis, Thrombosis, and Vascular Biology.2013; 33: 2252-2260
Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial.
Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: a randomized double-blind placebo-controlled clinical trial.
enrolling 378 patients. The corresponding I2 values all were 0% (P = 0.42). Pooled results from the fixed-effect model revealed that GLP-1RAs significantly decrease EDT (WMD, –9.96 milliseconds; 95% CI, –18.52 to –1.41; P = 0.02) (Figure 6). EDT is the time for blood flow velocity to drop from E wave to baseline and is prolonged when diastolic function is slightly impaired.
Sensitivity Analysis and Publication Bias
Sensitivity analysis did not report a significant impact of any individual trial on the overall results (see Supplemental Figure 3). Also, no evidence was found for publication bias by Egger's tests for heart failure hospitalization (t = –1.26; P = 0.238), NT-proBNP (t = –1.80; P = 0.169), 6MWT (t = –0.34; P = 0.755), QoL score (t = –0.60; P = 0.658), E wave (t = –1.27; P = 0.294), A wave (t = 2.79; P = 0.068), E/A ratio (t = –0.02; P = 0.987), or the E/e′ ratio (t = 0.76; P = 0.492). However, publication bias was assessed by Egger's tests for LVEF (t = 2.38; P = 0.037) and EDT (t = 4.26; P = 0.024), and we then used the trim-and-fill method to assess the stability of consolidation results. After including data from 5 virtual studies for LVEF (see Supplemental Figure 4) and 3 virtual studies for EDT (see Supplemental Figure 5), pooled results from the fixed-effect model showed that GLP-1RAs still do not significantly influence LVEF percentages (WMD, –0.67%; 95% CI, –1.46 to 0.46; P = 0.10), and GLP-1RAs still significantly decrease EDT (WMD, –14.1 milliseconds; 95% CI, –21.79 to –6.42; P < 0.001), which means that after completing the studies, the results were not reversed, and therefore the consolidated results are robust.
Discussion
In the present study, a meta-analysis of the effect of GLP-1RAs on heart failure was conducted. The pooled results showed that GLP-1RA could decrease the risk of heart failure hospitalization in those with no history of heart failure and increase the distances of 6MWT, but its effects on heart failure hospitalization with heart failure history, NT-proBNP levels, and QoL score were insignificant. GLP-1RAs had no significant on LVEF but significantly decreased E-wave velocity, E/A ratio, E/e′ ratio, and EDT. These results suggest that GLP-1RAs do not improve heart failure prognosis but have potential clinical benefit on ventricular diastolic function.
Recently, several systematic reviews had recognized that GLP-1RAs could improve heart failure hospitalization in patients with T2DM,
Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. The Lancet.
and we found that the improvement exists even in nondiabetic patients. In the present study, a significant decline in heart failure hospitalization was found in patients with no history of heart failure but not in patients with a history of heart failure. The possible reasons are, on one hand, that the benefits of GLP-1RAs on heart failure hospitalization may be connected to the cardiac functional status of patients; on the other hand, the effect of reduced heart failure hospitalization risk may be associated with a decreased risk of myocardial infarction in patients treated with GLP-1RAs.
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
6MWT, NT-proBNP, and QoL can be used to evaluate cardiac function and prognosis in patients with heart failure. Our results showed that treatment with GLP-1RAs significantly increased 6MWT compared with the control group but with no significant changes in NT-proBNP or QoL. The increase in 6MWT may be attributed not only to improvements in heart failure but also to reductions in cardiovascular events such as peripheral vascular disease and myocardial ischemia in patients with GLP-1RAs.
Lower risk of death and cardiovascular events in patients with diabetes initiating glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors: a real-world study in two Italian cohorts.
In conclusion, no change in heart failure hospitalization among patients with a history of heart failure, no change in NT-proBNP levels, and QoL indicates that GLP-1RAs do not improve the prognosis of heart failure.
The present study found that GLP-1RAs did not significantly alter LVEF, which is different from previous meta-analysis that included both RCT and cohort studies.
The varied findings may be related to the different types of studies included in the meta-analysis. It has been found that liraglutide enhances cardiac systolic function by reducing collagen deposition and fibrosis in rats.
Liraglutide attenuates cardiac remodeling and improves heart function after abdominal aortic constriction through blocking angiotensin II type 1 receptor in rats.
Drug Design, Development and Therapy.2019; 13: 2745-2757
The improvement of ventricular systolic function was not significant in patients treated with GLP-1RAs according to our findings. Interestingly, the present results indicate that GLP-1RA treatment reduced E-wave velocity, E/A ratio, E/e′ ratio, and EDT compared with the control group, suggesting that GLP-1RAs improved ventricular diastolic function. Previous animal studies have found that treatment with liraglutide improves ventricular diastolic function in heart failure with preserved ejection fraction (HFpEF) mice
The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction.
Glucagon-like peptide-1 analog liraglutide attenuates pressure-overload induced cardiac hypertrophy and apoptosis through activating ATP sensitive potassium channels.
The possible explanation for the improvement in diastolic function by GLP-1RAs may rely on the reduction of body weight, as obesity is associated with an increased risk of cardiac diastolic dysfunction. To summarize, there is a slight improvement in ventricular diastolic function after GLP-1RA treatment. The prevalence of HFpEF with reduced ventricular diastolic function is gradually increasing. Hence, GLP-1RAs possibly contribute to the prevention of HFpEF. Research in this area is worthwhile and should be continued.
Despite the valuable findings obtained in the present study, some limitations remain. First, in our meta-analysis, we did not analyze other primary drug treatments taken by patients that may have influence cardiac function such as spironolactone. Second, because the ventricular diastolic function is improved, when exploring the risk of heart failure hospitalization in patients with a history of heart failure, the original RCTs did not group patients into heart failure with reduced ejection fraction and HFpEF; thus, the effect of heart failure with reduced ejection fraction and HFpEF on the heart failure hospitalization could not be explored. Third, variability in echocardiographic estimates of ventricular structural changes may exaggerate or ignore treatment effects, leading to interstudy heterogeneity. Even with these limitations, we this paper confirmed the relationship between heart failure progress, cardiac function, and GLP-1RAs.
Conclusions
To our knowledge, this report is the first using an RCT meta-analysis of GLP-1RAs on heart failure admissions, progression, and ventricular function in patients with or without diabetes. Although no significant reduction in heart failure hospitalization was found in patients taking GLP-1RAs, the diastolic function according to echocardiography was significantly improved by GLP-1RAs. An RCT of patients with diabetes and HFpEF is worthwhile to explore the effect of GLP-1RAs on cardiac function and prognosis of heart failure.
Declaration of Interest
None declared.
Acknowledgments
This project was supported by grants from the National Natural Science Foundation of China (No. 81870336 to D.Q.P.).
All authors contributed to the study design; Dr Huixing and Di screened and extracted the information from studies and wrote the manuscript; and Dr Huixing analyzed the data. All authors reviewed drafts and approved the final version of the manuscript. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
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