Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: randomized placebo-controlled trial

Abstract

Background: Liraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease.

Methods: Patients with DM2 were randomly assigned to receive liraglutide 1.8 mg/day or placebo in this double-blind trial of 26 weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported.

Results: 23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (- 56 mL/s (- 91 to - 21)), E/A ratio (- 0.17 (- 0.27 to - 0.06)), Edec (- 0.9 mL/s2 * 10-3 (- 1.3 to - 0.2)) and E/Ea (- 1.8 (- 3.0 to - 0.6)), without affecting A (3 mL/s (- 35 to 41)) and Ea (0.4 cm/s (- 0.9 to 1.4)). Liraglutide reduced stroke volume (- 9 mL (- 16 to - 2)) and ejection fraction (- 3% (- 6 to - 0.1)), but did not change cardiac output (- 0.4 L/min (- 0.9 to 0.2)), cardiac index (- 0.1 L/min/m2 (- 0.4 to 0.1)) and peak ejection rate (- 46 mL/s (- 95 to 3)).

Conclusions: Liraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Trial registration ClinicalTrials.gov: NCT01761318.

Keywords: Cardiac function; Diabetes mellitus type 2; Diastolic heart failure; GLP1-receptor agonist; Liraglutide.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Trial profile. Patients were randomized with stratification according to sex and insulin use. One patient in liraglutide group withdrew consent before he ever received study drug. This patient was therefore not included in intention-to-treat analysis. In another patient assigned to liraglutide, withdrawal had taken place upon repeated hypoglycaemic events (on further examination this patient had positive anti-glutamic acid decarboxylase autoantibody titer and undetectable c-peptide levels consistent with type 1 diabetes mellitus). In the placebo group, one patient was lost to follow-up because he was in detention. All other patients reached end of study. ITT intention-to-treat

Fig. 2

LV diastolic function. Bar graphs of MR-derived indices of LV diastolic function. Blue bars indicate baseline measurement and red bars follow-up. Ea reflects the early peak longitudinal annular motion that is dependent on LV myocardial relaxation. E/Ea is the MR estimate of LV filling pressure. NS not significant

Fig. 3

LV systolic function. Bar graphs of MRI-derived indices of systolic function. Blue bars indicate baseline measurement and red bars follow-up. In the liraglutide group stroke volume decreased, whereas cardiac index remained unchanged because of the increased heart rate. Bpm beats per minute

Fig. 4

Pressure-volume relation. The LV filling pressure estimate E/Ea plotted against LV end-diastolic pressure (LVEDV). Liraglutide treatment (squares; blue = baseline, red = follow-up) results in a lower E/Ea and LVEDV, whereas placebo treated patients (circles; blue = baseline, red = follow-up) have higher E/Ea and LVEDV at follow-up then at baseline. Note that the shift in pressure volume curve is in opposite directions for liraglutide versus placebo. There was a tendency towards improved compliance in the liraglutide group