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

Abstract

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 µmol/g/min (0.013, 0.049); liraglutide, 0.055 µmol/g/min (0.019, 0.105); detemir plus liraglutide, 0.037 µmol/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.

Trial registration: ClinicalTrials.gov NCT01232946.

Figures

Figure 1.

Flow of study participants. One participant in the detemir-only arm died of non-study-related causes during randomized treatment.

Figure 2.

Achieved insulin, glucose, and fatty acid concentrations at the time of the PET measurements. Bars represent median values and whiskers represent upper 75th percentile values. Insulin concentrations were significantly different across the three groups, with significance in the pairwise comparison of detemir groups vs. liraglutide alone. The other measures were not significantly different between groups. NEFA, nonesterified fatty acid.

Figure 3.

MBF, MVO2, and work efficiency. Bars represent median values and whiskers represent upper 75th percentile values. Only liraglutide alone showed lower blood flow and greater work efficiency than the other two groups. RPP, rate-pressure product.

Figure 4.

Myocardial fuel consumption. Bars represent median values and whiskers represent upper 75th percentile values. There were no significant differences across groups in these measures. MFAE, myocardial fatty acid esterification; MFAO, myocardial fatty acid oxidation; MGU, myocardial glucose uptake.