Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection vs. Insulin Alone in Type 2 Diabetes

Context: It is unclear if effects of glucagon-like peptide-1 (GLP-1) and clinically available GLP-1 agonists on the heart occur at clinical doses in humans, possibly contributing to reduced cardiovascular disease risk. Objective: To determine whether liraglutide, at clinical dosing, augments myocardial glucose uptake (MGU) alone or combined with insulin compared with insulin alone in metformin-treated type 2 diabetes mellitus (T2D). Design: In a randomized clinical trial of patients with T2D treated with metformin plus oral agents or basal insulin, myocardial fuel use was compared after 3 months of treatment with insulin detemir, liraglutide, or combination detemir plus liraglutide added to background metformin. Main Outcome Measures: Myocardial blood flow (MBF), fuel selection, and rates of fuel use were evaluated using positron emission tomography, powered to demonstrate large effects. Results: MBF was greater in the insulin-treated groups [median (25th, 75th percentile): detemir, 0.64 mL/g/min (0.50, 0.69); liraglutide, 0.52 mL/g/min (0.46, 0.58); detemir plus liraglutide, 0.75 mL/g/min (0.55, 0.77); P = 0.035 comparing three groups, P = 0.01 comparing detemir groups to liraglutide alone]. There were no evident differences among groups in MGU [detemir, 0.040 mmol/g/min (0.013, 0.049); liraglutide, 0.055 mmol/g/min (0.019, 0.105); detemir plus liraglutide, 0.037 mmol/g/min (0.009, 0.046); P = 0.68 comparing three groups]. There were no treatment-group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. Conclusion: These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection.