Weight Change as Mediator for Cardiovascular Benefits of Novel Diabetes Medications: A Meta-Regression Analysis

Background: Prior research suggests cardiovascular (CV) benefits of glucose-lowering interventions are mediated by bodyweight changes, either through changes in fluid retention or body fat mass. For example, a meta-regression analysis of 30 randomized trials on glucose lowering interventions showed a 1 kg weight decrease was associated with a 5.9% (95% CI 3.9 - 8.0) relative reduction of heart failure risk (Ghosh et al., 2020) . We evaluated heterogeneity of CV benefits by weight change for two novel diabetes medications that lower weight: sodium glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) . Methods: We performed meta-regression analyses of published CV outcome trials (6 on SGLT2i, 8 on GLP-1RAs) using reported hazard ratios (HRs) and bodyweight difference across study arms. Dependent variables included log HRs for 1) all-cause mortality, 2) major adverse cardiovascular events (MACE) , and 3) hospitalization for heart failure. We ran linear mixed models with weights equal to the inverse of the variance of each study’s log HR. Results: The slopes from meta-regressions by pooling all trials and by drug type (Figure) were not significant and in some cases demonstrated an inverse relationship (SGLT2i for MACE, slope= -.102; p= .04) . Conclusion: We could not reproduce findings of increased CV benefits with more weight loss for SGLT2i and GLP-1RAs. Disclosure J.M.Rodriguez-valadez: None. W.Max: None. K.Fleischmann: None. B.Ferket: None. M.Hunink: None. U.Masharani: Advisory Panel; Ryse Health, Research Support; Clementia Pharmaceuticals. J.Yeboah: None. M.Park: Advisory Panel; Otsuka America Pharmaceutical, Inc., Reata Pharmaceuticals, Inc., Other Relationship; Merck & Co., Inc. L.Li: None. E.Weber: None. Y.Li: None. A.Berkalieva: None. Funding Research reported in this publication was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R01HL153456. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.