Pleiotropic effects of GLP‐1 receptor agonists on peripheral artery disease: Is there any hope?

Cardiovascular outcome trials (CVOTs) involving GLP-1 receptor agonists (GLP-1RAs) have conquered the attention of scientists and clinicians with the unexpected promise of cardio-renal benefits beyond their cardiovascular safety.1 In addition to their glucose-lowering effect, GLP-1RAs are associated with weight loss, low risk of hypoglycaemia, and benefits on the whole metabolic outlook, which may contribute to improve the cardiovascular risk profile of people with type 2 diabetes (T2DM).2, 3 Interestingly, the reduced incidence of major cardiovascular events (MACE) appears more evident, although not significantly, in people with T2DM and history of previous cardiovascular disease (CVD).3 Of note, the majority of people with T2DM have no established CVD4; therefore, the emerging real-world evidence showing cardiovascular benefits of GLP-1RAs in this population should be considered relevant, as they are associated with the reduction in composite cardiovascular outcomes, MACE, all-cause mortality, myocardial infarction, stroke, cardiovascular death and peripheral artery disease (PAD).5, 6 Accordingly, the joint consensus released by the American Diabetes Association and the European Association for the Study of Diabetes has recommended both GLP-1RAs and sodium glucose transporter-2 inhibitors as the first-line therapy to reduce the cardio-renal risk in people with T2DM.7 In this scenario, GLP-1RAs have been investigated for several pleiotropic effects, which seem to involve both cardiac and endothelial functions as well as cardiovascular risk factor modification.8, 9 There is evidence that endogenous GLP-1 plays a role in angiogenesis, promotes arterial vasodilation and mediates an anti-atherosclerotic effect in both preclinical and clinical studies.10, 11 Exenatide was first related to the proliferation of coronary artery endothelial cells and nitric oxide-induced vasodilation in people with T2DM.12 Similarly, peripheral vasodilation and reduction of oxidative stress, as well as decrease in inflammation and intima-media thickness, were described in both preclinical and observational prospective studies with liraglutide.10, 13 The potential anti-atherosclerotic and anti-inflammatory effects of GLP-1RAs may participate in the significant reduction of MACE in people with T2DM resulting from CVOTs.3, 14 PAD and diabetic foot ulcers were not among the primary outcomes of CVOTs; however, a post hoc analysis from LEADER trial reported a reduction in lower limb amputations in people assigned to liraglutide.15 GLP-1RAs may improve arterial stiffness and determine systemic microcirculatory benefits in the peripheral vascular district (Figure 1). Particularly, the activation of GLP-1 receptors on peripheral vessels may promote the remodelling of arterial walls, reducing the intima-media thickness and conferring stability to the atherosclerotic plaque.8, 16 Moreover, GLP-1RAs seem able to regulate apoptosis and inflammatory markers circulating levels,8 as emerged from clinical studies relating liraglutide to a reduction of tumour necrosis factor-alpha, plasminogen activator inhibitor-1, interleukin 1-beta and interleukin 6 levels.17 Furthermore, the peripheral vasodilation associated with GLP-1RAs may be determined by direct relaxation of vascular smooth muscles and mediated by neurohormonal and local factors in a mouse model.16 Potential GLP-1 receptor agonists (GLP1-RAs) effect on peripheral artery disease (PAD). ↑: increase in circulating levels/improvement. ↓: decrease in circulating levels/reduction. Cardiac function refers to myocardiocytes metabolism and chronotropic/inotropic effect on cardiac muscle. EC, endothelial cells; EPC, endothelial progenitor cells; IL-1β, interleukin 1beta; IL-6, interleukin 6; NO, nitric oxide; PAI, plasminogen activator inhibitor; ROS, reactive oxygen species; TNF-α, tumour necrosis factor alpha; and VEGF, vascular endothelial growth factor. Of interest, GLP-1 may increase circulating levels of endothelial progenitor cells supporting their biological function, which may determine the autocrine and paracrine release of the vascular endothelial growth factor (VEGF) in people with T2DM. VEGF is involved in vascular cell proliferation and differentiation, promoting both endothelial homoeostasis and angiogenesis.11, 18 The potential benefits of GLP-1RAs on PAD may represent a significant plot twist of this highly misdiagnosed complication. Although PAD has been included among the criteria to establish the history of previous CVD in CVOTs, it has never been evaluated as a primary or even secondary outcome, with the exception of SUSTAIN-6 trial.19 Most CVOTs assessed peripheral vascular events as not specified vascular disorders. There were no differences in the incidence of peripheral vascular events between intervention and placebo groups across the trials, except for REWIND and SUSTAIN-6 (Table 1). Interestingly, Exenatide LAR in EXSCEL was associated with a reduction, although not significant, in the incidence of PAD compared with placebo. This may suggest a certain beneficial effect on peripheral vascular events associated with once-weekly GLP-1RAs over once-daily molecules. On the other hand, studies investigating PAD prevalence, as well as its progression and treatment, in people with diabetes are scanty20, 21 due to several criticisms in terms of diagnosis and follow-up (Table 2). However, the early detection and treatment of PAD, associated with the effective management of other traditional risk factors, may contribute to prevent the onset of diabetic ulcers and improve their prognosis, with a reduction in the lower limb amputation rate.22, 23 PAD is not included in the outcomes of CVOTs The definition of PAD is not standardized in clinical trials PAD is often referred as a complication of diabetic foot ulcers PAD evaluation in clinical trials should include peripheral revascularisation and lower extremity amputation secondary to limb ischaemia Lack of a specific biomarker and/or limited accessibility to a reproducible functional parameter to evaluate the progression of PAD Extreme variability of clinical symptoms Three trials are currently ongoing in people with T2DM to investigate the contribution of GLP-1RAs on peripheral perfusion. One trial (NCT04560998) tested semaglutide versus placebo on maximum walking distance on a constant load treadmill test at baseline and after 52 weeks of treatment. Among the other two trials involving liraglutide, the first one (NCT04146155) was a multicenter study aimed at assessing the efficacy of 24 weeks of treatment on pain-free walking distance. The other one (NCT04881110) is entitled “Effects of the GLP-1RA Liraglutide on Lower Limb Perfusion in people with T2DM and PAD: a Randomized Controlled Trial (STARDUST)”. The trial included people with suboptimal glycaemic control (HbA1c 6.5%–8%) treated with metformin and/or insulin who were randomized to receive liraglutide or intensify the current anti-diabetes therapy. Both groups have been addressed to the adequate control of major atherosclerosis risk factors, with adjustment or confirmation of the other pharmacological therapies (lipid lowering, anti-hypertensive, and platelet anti-aggregants/anti-coagulants therapies). The primary outcome was to assess the change in peripheral perfusion through the measurement of transcutaneous oxygen pressure (TcPO2) at baseline and after 3 and 6 months of treatment, offering for the first time an objective and reproducible parameter of PAD.20 Indeed, TcPO2 precisely reflects the status of lower limb perfusion, addressing the peripheral oxygen requirement and determining levels and needs of surgical procedures (revascularisation, amputation). Moreover, TcPO2 results are not impaired by arterial calcification, which may affect the reliability of other diagnostic evaluations, such as ankle brachial index.24 The effect of PAD on ulcers and lower limb amputation is a substantial concern in people with T2DM; therefore, the opportunity to improve the PAD management may represent an outstanding chance. The need of new data on peripheral circulation is clearly growing and is reflected by the purposes of the trials, which are investigating the effect of GLP1-RAs on people with T2DM and PAD. Results from these trials are warranted to confirm evidence from preclinical and clinical studies which linked GLP-1RAs to a protective effect and hence a potential benefit on vascular complications. Perhaps, clinicians are ready to “put their (diabetic) feet down”. Paola Caruso, Maria Ida Maiorino, and Giuseppe Bellastella wrote the manuscript. Katherine Esposito and Dario Giugliano critically reviewed the manuscript. All the authors have read and approved the final manuscript. Open Access Funding provided by Universita degli Studi della Campania Luigi Vanvitelli within the CRUI-CARE Agreement. The authors declare no conflicts of interest. Not applicable. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/dmrr.3627. The data reported in this study are publicly available in the literature.