Introduction

Type 2 diabetes mellitus (T2DM) and obesity are 2 very commonly met and coexisting diseases, tightly implicated in heart failure (HF) and coronary artery disease. In everyday practice, dedicated lifestyle modification including an appropriate diet, combined with exercise and medical treatment, provides substantial benefits regarding cardiovascular (CV) outcomes. In recent years, 2 very promising classes of drugs, glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter type 2 (SGLT-2) inhibitors, can be used either as first-line antidiabetic therapy in drug-naive patients or as add-on therapy in patients already being treated with metformin, enriching our armamentarium for the treatment of T2DM.¹ Both previously mentioned antidiabetic agents exhibited several additional benefits in patients with concomitant atherosclerotic cardiovascular disease (ASCVD) and high or very high CV risk, which are largely independent from the simple normalization of blood glucose levels. The CV-protective effect of GLP1-RAs is mainly linked to the inhibition of atherosclerosis development and progression, whereas those effects of SGLT-2 inhibitors are mainly linked to the improvement of renal function and the reduction of hospitalizations and mortality in patients with HF. In the latter clinical condition, GLP1-RAs failed to show substantial clinical benefits in randomized controlled trials and thus are not indicated.^1,2 Possible explanations for the paucity of positive effects of GLP1-RAs in the HF population may be that additional body weight reduction, on top of preexisting loss of lean muscle body mass and cachexia, and drug-induced positive chronotropy are unwanted or even detrimental effects on HF treatment. Nevertheless, recommendations for the use of both drug classes, GLP-1RAs and SGLT-2 inhibitors, have expanded beyond their initial metabolic targets, as currently more mechanistic insights, including gross CV system changes, elimination of inflammation, improvement of endothelial function and microcirculation, and potential alterations in the intracellular milieu are being elucidated.² This might implicate some of the pleiotropic effects of these agents, such as cell protection against the reperfusion injury of an ischemic/reperfused myocardium, or the more efficient use of energy substrates, all of these effects expanding beyond the inhibition of the inflammatory process.³ The previously mentioned drug effects may explain the wide range in clinical outcomes, which are independent from insulin release, inhibition of glucagon secretion, and the delay in gastric emptying or satiety mediated by GLP-1RAs. Nevertheless, the coadministration of other drugs may enhance or abrogate the effects of GLP-1RAs, leading to some conflicting evidence in clinical outcomes.² Of note, because of the heterogeneity of possible various confounders in clinical studies with GLP-1RAs, current recommendations may extend from no specific indications in patients with T2DM to patient populations with established ASCVD risks, or even considering the use of GLP-1RAs in patients with HF under certain circumstances.¹

Reverse translational research is increasing, with enhanced interest in interpreting the underlying mechanisms by which positive clinical outcomes are obtained. Liraglutide is a long-acting GLP1-RA that is recommended in patients with T2DM and ASCVD or high to very high CV risk to reduce CV events or the risk for death.^1,3 In a study reported in this issue of JACC: Basic to Translational Science, Punjabi et al⁴ tested the hypothesis that liraglutide administration is associated with down-regulation of endothelial vascular cell adhesion molecule (VCAM)-1 expression, irrespective of glucose levels, in an atherosclerotic murine model. By using contrast-enhanced ultrasound molecular imaging with a microbubble contrast agent in apolipoprotein E–knockout mice, the investigators found that the GLP1-RA liraglutide results in the down-regulation of the VCAM-1 signal on the vascular endothelium in vivo, reducing the proinflammatory agents and attenuating plaque formation, independently of plasma glucose, glycated hemoglobin, and cholesterol levels. They also measured a number of cytokines, which are implicated in the mechanism of inflammation.

The study sheds light on the inflammatory hypothesis, providing important information with respect to alterations in endothelial VCAM-1 expression. Interestingly, some of the drug effects are time dependent and others not. According to this, plasma tumor necrosis factor-α, interleukin-1β, monocyte chemoattractant protein-1, and osteopontin levels required longer time to decrease. In a significant number of cytokines that were examined, part of the changes observed are critical for the mechanism of inflammation, whereas others may just be epiphenomena without further roles.

The results of the study confirmed the gradual decrease in body weight of the animals, with an early increased rate of body weight reduction shortly after liraglutide administration and a later constant rate of reduction throughout the observational period, similar to that observed in the vehicle group. Regarding the metabolic changes, some divergent findings with respect to levels of lipids exist. Although the results were consistent with the decrease in triglycerides, inconsistencies were noted in the changes of cholesterol levels, showing that liraglutide’s effect weakens over time.⁴ Additionally, full-blood glycated hemoglobin levels <4% in both the vehicle- and the liraglutide-treated groups, in conjunction with the aforementioned changes in lipids, clearly show a diversion between CV benefits and glycemic or lipidemic profiles.

The investigators used only a fixed dose of liraglutide, raising the question of whether a higher dose may have delivered a faster response or may provide additional beneficial effects. Along this line, we may also assume that the chosen dose of liraglutide might have been low and thus insufficient to exert the positive chronotropic effect of the drug and increase heart rate, as expected and described in many clinical studies.³

Liraglutide prevents atherosclerosis, improves plaque stability scores, and exerts cytoprotective and metabolic actions on cardiomyocytes. The present study provides very useful information regarding the aorta. However, there is a lack of information regarding the inflammatory process, or the prevention of local atherosclerosis development and plaque instability score from the coronary arteries. This particular type of information would be very useful for clinical expression and outcomes in coronary artery disease. GLP-1RAs and SGLT-2 inhibitors interfere with the mechanism of reduction of reperfusion injury.^2,3,5 Lethal reperfusion injury occurs after a series of alterations in intracellular transduction signaling cascade, resulting in the opening of the mitochondrial permeability transition pores, destruction of the mitochondria, and consecutively to myocardial cell death. This can be prevented by the modification of some intracellular pathways, inhibiting the opening of the mitochondrial permeability transition pores, thus maintaining mitochondrial integrity and myocardial cell survival. Additional evidence from the intracellular milieu, obtained after liraglutide administration, would be interesting, as other studies, using different SGLT-2 inhibitors, have previously shown significant changes in prosurvival pathways.⁵ However, some questions from the study of Punjabi et al⁴ remain open: whether the findings after liraglutide administration are related only to a specific substance effect, namely, the difference between a drug or a drug class effect; whether the drug dose is sufficient; whether there are additional vascular changes in the coronary arteries; and finally whether there are additional alterations in the intracellular transduction signaling. Reverse translational research has taken lessons from the bedside and transfers clinical experience to the bench, in order to exploit more findings from basic research studies. Beyond the class effects of GLP-1RAs and SGLT-2 inhibitors, the individual drug effect of each class of medication, the route of administration, the duration of treatment, drug coadministration and drug-to-drug interactions, possible side effects and relative contraindications, and finally patient preference and compliance should be taken into consideration. Both antidiabetic drug classes do not cause (at least severe) hypoglycemia, but more caution is needed in their coadministration with other antidiabetic agents. More experimental studies are continuously reporting insights into the mechanisms of reductions in major adverse CV events, clinical deterioration, hospitalization, and death.

Footnotes