The treatment of type 2 diabetes (T2D) with liraglutide results in significant improvements in myocardial perfusion, energetics and 6-minute walking distance, reports a new study, which also finds that pioglitazone has no effect on these parameters. Researchers attribute the glucagon-like peptide-1 receptor agonist’s (GLP-1 RA) efficacy to its ability to keep higher circulating concentrations of vascular endothelial growth factor and stromal cell derived factor-1 alpha, as well as its effects on endoplasmic reticulum (ER) function. In contrast, the researchers suggest the effects of insulin sensitizing thiazolidinedione (TZD) and pioglitazone on diastolic function are not related to myocardial metabolism but rather an improved myocardial compliance. “Supporting this notion, left ventricular (LV) concentricity correlated with mitral-inflow E/A ratio,” said the team, which was led by Amrit Chowdhary, PhD, from the Leeds Institute of Cardiovascular and Metabolic Medicine in the UK. Main findings Results from the study, which appears in the August 6 issue of the Journal of the American College of Cardiology, found that Liraglutide treatment increases stress myocardial blood flow (1.62 mL/g/min [95% confidence interval [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). Myocardial perfusion reserve is also increased (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). Liraglutide treatment also significantly increased the 6-minute walk distance (488 m [95% CI: 458-518 m] to 521 m [95% CI: 481-561 m]; P=0.009). “Our study complements the findings of the SELECT trial by showing significant improvements in perfusion and energetics in the T2D cohort despite a modest reduction of 3.07% (95% CI: 2.04%-4.11%) in body weight with liraglutide,” said the authors of the paper, which was also published Monday online. “Taken together, these findings from GLP-1 RA trials suggest that similar to sodium-glucose cotransporter 2 inhibitors, this class of drugs likely will not remain in the therapeutic landscape only as diabetes or weight loss drugs but may also be considered as medications for cardiovascular treatment.” Study commentary Silvio E. Inzucchi, MD from Yale School of Medicine in New Haven, Connecticut, and Andrew E. Arai, MD from the University of Utah School of Medicine in Salt Lake City, described the study as “adding substantially to the emerging body of knowledge concerning how GLP-1 RAs may improve CV risk beyond glycemic control alone.” In their editorial commentary of the randomized cross-over single-center study, the experts highlighted the fact that liraglutide improved myocardial perfusion and energetics whereas pioglitazone did not. “Although pioglitazone appeared to improve diastolic function, it was paradoxically associated with a trend towards higher filling pressures. “The latter should not be surprising given the sodium retentive properties of TZDs, particularly at higher doses.” Directional improvement Commenting on the importance of the directional improvement in phosphocreatine (PCr)/ adenosine triphosphate (ATP) ratio observed during treatment with liraglutide, the experts pointed out that the improvement was observed both at rest and during dobutamine stress. “Although we cannot fully know that improved perfusion or energetics will be the mechanism rendering one of these medications better for patients over the long-term than another, directionally, these changes appear to be favorable for liraglutide relative to pioglitazone,” they added. In closing, the experts said that the main difference between the two newer medication categories (GLP-1 RAs and sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the TZDs were their respective effects on adverse clinical heart failure (HF) outcomes. “The incidence is reduced with SGLT2i and GLP-1 RA (particularly the former) and increased with TZDs, although a recent post hoc report from IRIS suggests that this effect can in fact be mitigated by lower doses,” they added. Study methodology Forty-one T2D patients (age 63 years [95% CI: 59-68 years] of which 27 [66%] were male, and without cardiovascular disease were randomized to liraglutide or pioglitazone for a 16-week treatment. This was followed by an 8-week washout and a further 16-week treatment with the second trial drug. Participants underwent rest and dobutamine stress 31 phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance These methods were to measure the myocardial energetics index phosphocreatine to adenosine triphosphate ratio, myocardial perfusion, left ventricular (LV) volumes, systolic and diastolic function, before and after treatment. The 6-minute walk-test was used for functional assessments. The primary endpoint was change in myocardial perfusion after treatment with liraglutide and pioglitazone. Sources: Chowdhary A, Thirunavukarasu C, Joseph T, et al. Liraglutide Improves Myocardial Perfusion and Energetics and Exercise Tolerance in Patients With Type 2 Diabetes. J Am Coll Cardiol. 2024;84: 540–557. Inzucchi SE, Arai AE. Inquiries Into the Mechanisms by Which GLP-1 Receptor Agonists Reduce Cardiovascular Risk in Diabetes. J Am Coll Cardiol. 2024;84:558–560. Image Credit: onephoto – stock.adobe.com