Liraglutide Improves Myocardial Perfusion and Energetics and Exercise Tolerance in Patients With Type 2 Diabetes

Abstract

Background: Type 2 diabetes (T2D) is characterized by insulin resistance (IR) and dysregulated insulin secretion. Glucagon-like peptide-1 receptor agonist liraglutide promotes insulin secretion, whereas thiazolidinedione-pioglitazone decreases IR.

Objectives: This study aimed to compare the efficacies of increasing insulin secretion vs decreasing IR strategies for improving myocardial perfusion, energetics, and function in T2D via an open-label randomized crossover trial.

Methods: Forty-one patients with T2D (age 63 years [95% CI: 59-68 years], 27 [66%] male, body mass index 27.8 kg/m²) [95% CI: 26.1-29.5 kg/m²)]) without cardiovascular disease were randomized to liraglutide or pioglitazone for a 16-week treatment followed by an 8-week washout and a further 16-week treatment with the second trial drug. Participants underwent rest and dobutamine stress ³¹phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance for measuring the myocardial energetics index phosphocreatine to adenosine triphosphate ratio, myocardial perfusion (rest, dobutamine stress myocardial blood flow, and myocardial perfusion reserve), left ventricular (LV) volumes, systolic and diastolic function (mitral in-flow E/A ratio), before and after treatment. The 6-minute walk-test was used for functional assessments.

Results: Pioglitazone treatment resulted in significant increases in LV mass (96 g [95% CI: 68-105 g] to 105 g [95% CI: 74-115 g]; P = 0.003) and mitral-inflow E/A ratio (1.04 [95% CI: 0.62-1.21] to 1.34 [95% CI: 0.70-1.54]; P = 0.008), and a significant reduction in LV concentricity index (0.79 mg/mL [95% CI: 0.61-0.85 mg/mL] to 0.73 mg/mL [95% CI: 0.56-0.79 mg/mL]; P = 0.04). Liraglutide treatment increased stress myocardial blood flow (1.62 mL/g/min [95% CI: 1.19-1.75 mL/g/min] to 2.08 mL/g/min [95% CI: 1.57-2.24 mL/g/min]; P = 0.01) and myocardial perfusion reserve (2.40 [95% CI: 1.55-2.68] to 2.90 [95% CI: 1.83-3.18]; P = 0.01). Liraglutide treatment also significantly increased the rest (1.47 [95% CI: 1.17-1.58] to 1.94 [95% CI: 1.52-2.08]; P =0.00002) and stress phosphocreatine to adenosine triphosphate ratio (1.32 [95% CI: 1.05-1.42] to 1.58 [95% CI: 1.19-1.71]; P = 0.004) and 6-minute walk distance (488 m [95% CI: 458-518 m] to 521 m [95% CI: 481-561 m]; P = 0.009).

Conclusions: Liraglutide treatment resulted in improved myocardial perfusion, energetics, and 6-minute walk distance in patients with T2D, whereas pioglitazone showed no effect on these parameters (Lean-DM [Targeting Beta-cell Failure in Lean Patients With Type 2 Diabetes]; NCT04657939).

Keywords: cardiovascular magnetic resonance imaging; glucagon like peptide 1 receptor agonists; liraglutide; magnetic resonance spectroscopy, pioglitazone; type 2 diabetes.

Figure 1:. Cardiac ³¹phosphorus magnetic resonance spectroscopy (³¹P-MRS) protocol

After the completion of rest chemical shift imaging (CSI) acquisition, dobutamine was infused at incremental doses between 10 and 40μg/kg/min as necessary to achieve the target heart rate of 65% maximum (maximum heart rate calculated as 220 – age). The figure shows representative rest and dobutamine stress cardiac phosphorus spectra images. 2,3-DPG indicates 2,3-diphosphoglycerate; ATP, adenosine triphosphate; PCr, phosphocreatine; PDE, phosphodiesters.

Figure 2:. Multiparametric scan protocol.

Magnetic resonance imaging (MRI) protocol consisted of thoracic and abdominal water/fat images using a non-breath-hold multi-echo gradient echo (GRE) sequence, followed by cardiac cine imaging, pre- and post-contrast T1 mapping, perfusion imaging, velocity-encoded mitral in-flow imaging, and late gadolinium enhancement (LGE) imaging. Cine images, perfusion imaging and velocity-encoded mitral in-flow imaging were repeated at target heart rate of 65% maximum (maximum heart rate calculated as 220 – age) using an identical dobutamine infusion protocol to that of the dobutamine stress cardiac ³¹phosphorus magnetic resonance spectroscopy (³¹P-MRS) acquisition. The figure shows representative images from indicated cardiac sequences. LV indicates left ventricular.

Figure 3:. Consort flow diagram

Consort flow diagram showing the recruitment pathway with details of numbers of study patients with type 2 diabetes who were screened, assessed and randomised, followed allocated treatment and completed follow-up, and were included in data analysis.

Figure 4:. Myocardial changes due to the study medications

Box and Whisker plots demonstrating changes in (A) dobutamine stress myocardial blood flow (MBF), (B) myocardial perfusion reserve index (MPRI), (C) rest phosphocreatine to ATP ratio (PCr/ATP) and D) dobutamine stress PCr/ATP in the two treatment arms of the study.

Central illustration:. Changes in myocardial biomarkers due to treatment with liraglutide or pioglitazone.

Central illustration representing the study aims, design, findings and clinical implications. A significant increase in myocardial perfusion reserve index and myocardial energetics index as measured by PCr/ATP was seen after 16 weeks of liraglutide therapy for 16 weeks.