Glucagon-like peptide 1 based treatments preserve left ventricular diastolic function irrespective of body weight changes - a systematic review and meta-analysis

Background Activating the Glucagon-like peptide 1 (GLP-1) receptor has been shown to improve exercise capacity in obese patients with heart failure with preserved ejection fraction (HFpEF) but the mechanisms are poorly understood. Furthermore, it remains unclear if these effects are obesity-dependent and secondary to weight loss. Left ventricular diastolic dysfunction is a key component of HFpEF. We aimed to assess the effects of GLP-1 based treatments on diastolic function in various animal models of cardiac disorders using a meta-analytic approach. Methods We searched Medline via Ovid, Scopus and Web of Science from inception until September 2024 for preclinical studies investigating the effects of GLP-1 receptor agonists or dipeptidyl peptidase 4 (DPP-4) inhibitors on left ventricular diastolic function in any model of heart disease. To enclose all available measures of diastolic function while considering hierarchical dependency, we conducted a four-level meta-analysis. We employed meta-regression to explore sources of heterogeneity and contour-enhanced funnel plot to assess publication bias. Study quality was evaluated using the CAMARADES checklist. Results Of a total of 16912 studies screened, 57 fulfilled our inclusion criteria. Meta-analysis revealed that GLP-1 based treatments remarkably improve left ventricular diastolic function (Hedges' g = 1.05, 95% CI: 0.73 - 1.37, p < 0.0001). Meta-regression showed comparable effects between GLP-1 receptor agonists (Hedges' g = 0.93, 95% CI: 0.47 - 1.39, p < 0.001) and DPP-4 inhibitors (Hedges' g = 1.15, 95% CI: 0.68 - 1.63 p < 0.001). Nevertheless, the efficacy of GLP-1 treatments on diastolic function differs among disease models. While strong treatment effects were found in diabetic cardiomyopathy (Hedges’ g = 1.45, 95% CI: 0.92 - 1.98, p < 0.001) and myocardial infarction (Hedges’ g = 1.55, 95% CI: 0.69 - 2.34, p < 0.001), changes in pressure overload-induced cardiac dysfunction were not significant. Interestingly, we found no difference in effect size between obese and non-obese models. Furthermore, changes in diastolic function did not correlate with those in body weight. Conclusions Pharmacological activation the GLP-1 receptor may preserve left ventricular diastolic function. Their efficacy unlikely depends on drug class or the presence of obesity but may vary among etiologies of cardiac disorders. The impact of GLP-1 based treatments on diastolic function might therefore contribute to its cardioprotective effects in HFpEF irrespective of obesity and weight loss. The considerable effect size in myocardial infarction also suggests a possible role for GLP-1 in treating ischemic heart disease.