1351229 - Liraglutide treatment improves myocardial energetics and stress perfusion in patients with type 2 diabetes- A randomised, single centre, open label, cross-over drug trial

Both insulin secretion and resistance in Type 2 diabetes (T2D) is amenable to pharmacological intervention. Glucagon-like peptide-1 receptor agonists (GLP-1RA) promotes insulin secretion and is an important pharmacological target in T2D with a proven cardiovascular safety profile and beneficial cardiovascular outcomes^1,2. Pioglitazone is a peroxisome proliferator activated receptor gamma agonist which targets peripheral insulin sensitivity.  In a single center, open-label, randomized, cross-over design trial we sought to compare two distinct glycemic control strategies of 1) targeting beta-cell dysfunction (liraglutide), 2) insulin resistance (pioglitazone) results in greater improvements in myocardial perfusion, energetics and function in T2D.

Methods:

Fifty-two eligible patients with T2D and no known prior cardiovascular disease were randomized to one of the study drugs for a 16-week treatment period followed by an 8-week washout and a further 16-week second drug treatment period. Thirty-three eligible participants completed both treatment arms, while 5 patients withdrew after completing the pioglitazone treatment arm first (n=38). Participants have undergone ³¹phosphorus magnetic resonance spectroscopy (³¹P-MRS) at rest and dobutamine stress, and cardiac magnetic resonance (CMR) scans consisting of rest and dobutamine stress cine imaging, perfusion imaging/mapping and velocity-encoded mitral in-flow imaging before commencement and after completion of each treatment arm (four scans per participant). Intravenous dobutamine was infused, at incremental doses (10 to 40 µg/kg/min to achieve 65% of the age-predicted maximal heart rate).

Results:

Clinical and biochemical characteristics, and CMR/³¹P-MRS results are provided in Tables 1&2 respectively.
Liraglutide therapy resulted in significant reductions in the body mass index, with average weight loss of 1.7kg and significant improvements in glycemic control. The improvement in glycemic control was significantly higher with liraglutide compared to pioglitazone (p=0.03) and only liraglutide led to significant reductions in fasting blood glucose. Pioglitazone led to a significant increment in mean LV mass, while no significant effect in myocardial mass or mass index were detected with liraglutide. Liraglutide therapy resulted in increased rest and dobutamine stress energetics, global stress myocardial blood flow and myocardial perfusion reserve (MPR). With pioglitazone, only an isolated improvement in the rest diastolic function was observed.  The improvements in rest energetics and MPR with liraglutide were significantly higher compared to changes with pioglitazone.

Conclusion:

In this randomised cross-over study we showed for the first time that treatment with GLP-1RA liraglutide results in significant improvements in myocardial perfusion and energetics, while pioglitazone shows no effect in modulation of these parameters. Pioglitazone results in significant increases in LV mass and an isolated improvement in rest diastolic function.