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

Caruso, Paola; Maiorino, Maria Ida; Bellastella, Giuseppe; Esposito, Katherine; Giugliano, Dario

doi:10.1002/dmrr.3627

Cited by 5 publications

(11 citation statements)

References 34 publications

(58 reference statements)

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“…Liraglutide, as well as other GLP-1RAs, may determine its effect on peripheral perfusion through both microvascular and macrovascular mechanisms. Liraglutide is effective on glycometabolic outlook, which affects the cardiovascular risk profile . Particularly, GLP-1RAs regulate glucose blood levels and peripheral insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…Both preclinical and clinical studies have investigated the relationship among GLP-1RAs, vascular smooth muscle relaxation, and levels of inflammatory markers, including tumor necrosis factor α, plasminogen activator inhibitor 1, interleukin 1β, and interleukin 6, with a favorable effect on chronic systemic inflammation . Furthermore, the activation of the GLP-1 receptor may stimulate endothelial progenitor cells proliferation and differentiation, improving vascular homeostasis, angiogenesis, and plaque stability …”

Section: Discussionmentioning

confidence: 99%

“…28,29 Furthermore, the activation of the GLP-1 receptor may stimulate endothelial progenitor cells proliferation and differentiation, improving vascular homeostasis, angiogenesis, and plaque stability. 14,30 Peripheral artery atherosclerosis heavily contributes to lower-extremity complications and hospitalization, with high medical costs and severe clinical burden. 3 Moreover, PAD and its complications are responsible for the reduction of both life expectancy and quality, with a mortality rate that may overcome cancer mortality.…”

Section: Jama Network Open | Diabetes and Endocrinologymentioning

confidence: 99%

“…Moreover, a post hoc analysis from the LEADER (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes) trial described a significant reduction in lower-extremity amputations (hazard ratio, 0.65; 95% CI, 0.45-0.95; P = .03), mostly driven by major amputations rather than minor ones . This finding has been related to the liraglutide-induced improvement of several PAD risk factors as well as to pleiotropic effects that liraglutide may exert on the vascular system . Given its potential role in peripheral vascular disease, STARDUST (Effects of the GLP-1 Receptor Agonist Liraglutide on Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease: An Open-Label Randomized Clinical Trial) was designed to assess the effect of daily administered liraglutide on peripheral perfusion in a population of individuals with type 2 diabetes and PAD.…”

Section: Introductionmentioning

confidence: 99%

“… 13 This finding has been related to the liraglutide-induced improvement of several PAD risk factors as well as to pleiotropic effects that liraglutide may exert on the vascular system. 10 , 14 Given its potential role in peripheral vascular disease, STARDUST (Effects of the GLP-1 Receptor Agonist Liraglutide on Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease: An Open-Label Randomized Clinical Trial) was designed to assess the effect of daily administered liraglutide on peripheral perfusion in a population of individuals with type 2 diabetes and PAD.…”

Section: Introductionmentioning

confidence: 99%

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Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease

Caruso,

Maiorino,

Longo

et al. 2024

JAMA Netw Open

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ImportancePeripheral artery disease (PAD) in diabetes may lead to diabetic foot ulcer and lower-extremities amputation. Glucagon-like peptide 1 receptor agonists have proven cardiovascular benefits in trials of people with type 2 diabetes at high cardiovascular risk.ObjectiveTo examine the effect of liraglutide on peripheral perfusion measured as peripheral transcutaneous oxygen pressure (TcPo2) in individuals with type 2 diabetes and PAD.Design, Setting, and ParticipantsThis open-label randomized clinical trial was conducted between February 1, 2021, and June 30, 2022, with a final follow-up on December 30, 2022, at University of Campania “Luigi Vanvitelli,” Naples, Italy. Fifty-five individuals with type 2 diabetes, PAD, and TcPo2 between 30 and 49 mm Hg were included.InterventionsPatients were randomized to receive 1.8 mg of subcutaneous liraglutide or conventional treatment of cardiovascular risk factors (control group) for 6 months.Main Outcomes and MeasuresCoprimary outcomes were the change from baseline of peripheral perfusion between groups and the comparison of the proportion of individuals who reached 10% increase of TcPo2 from baseline in each group.ResultsFifty-five participants (mean [SD] age, 67.5 [8.5] years; 43 [78%] male) were randomized (27 to the liraglutide group and 28 to the control group) and analyzed. Participants had a median (IQR) hemoglobin A1c level of 6.9% (6.5%-7.8%) and a mean (SD) TcPo2 of 40.3 (5.7) mm Hg. Transcutaneous Po2 increased over time in both groups, with significant differences favoring the liraglutide group after 6 months (estimated treatment difference, 11.2 mm Hg; 95% CI, 8.0-14.5 mm Hg; P &lt; .001). The 10% increase of TcPo2 occurred in 24 participants (89%) in the liraglutide group and 13 (46%) in the control group (relative risk, 1.91; 95% CI, 1.26-2.90; P &lt; .001). Compared with the control group, individuals in the liraglutide group had a significant reduction of C-reactive protein (−0.4 mg/dL; 95% CI, −0.7 to −0.07 mg/dL; P = .02), urinary albumin to creatinine ratio (−119.4 mg/g; 95% CI, −195.0 to −43.8 mg/g; P = .003), and improvement of 6-minute walking distance (25.1 m; 95% CI, 21.8-28.3 m; P &lt; .001).Conclusions and RelevanceIn this randomized clinical trial of people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion detected by TcPo2 measurement during 6 months of treatment. These results support the use of liraglutide to prevent the clinical progression of PAD in individuals with type 2 diabetes.Trial RegistrationClinicalTrials.gov Identifier: NCT04881110

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Jama Network Open | Diabetes and Endocrinologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease

Caruso,

Maiorino,

Longo

et al. 2024

JAMA Netw Open

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GLP-1 receptor agonists’ impact on cardio-renal outcomes and mortality in T2D with acute kidney disease

Pan,

Chen,

Chen

et al. 2024

Nat Commun

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Previous studies have explored the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in reducing cardiovascular events in type 2 diabetes. Here we show that GLP-1 RAs are associated with lower risks of mortality, major cardiovascular events (MACEs), and major adverse kidney events (MAKEs) in type 2 diabetes patients with acute kidney disease (AKD). Utilizing global data from the TriNetX database (2002/09/01-2022/12/01) and propensity score matching, we compare 7511 GLP-1 RAs users to non-users among 165,860 AKD patients. The most common causes of AKI are sepsis (55.2%) and cardiorenal syndrome (34.2%). After a median follow-up of 2.3 years, GLP-1 RAs users exhibit reduced risks of mortality (adjusted hazard ratio [aHR]: 0.57), MACEs (aHR: 0.88), and MAKEs (aHR: 0.73). External validation in a multicenter dataset of 1245 type 2 diabetes patients with AKD supports the favorable outcomes. These results emphasize the potential of GLP-1 RAs in individualized treatment for this population.

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Challenges and opportunities in the management of type 2 diabetes in patients with lower extremity peripheral artery disease: a tailored diagnosis and treatment review

Mahé,

Aboyans,

Cosson

et al. 2024

Cardiovasc Diabetol

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Lower extremity peripheral artery disease (PAD) often results from atherosclerosis, and is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Individuals with T2DM exhibit a more severe manifestation and a more distal distribution of PAD compared to those without diabetes, adding complexity to the therapeutic management of PAD in this particular patient population. Indeed, the management of PAD in patients with T2DM requires a multidisciplinary and individualized approach that addresses both the systemic effects of diabetes and the specific vascular complications of PAD. Hence, cardiovascular prevention is of the utmost importance in patients with T2DM and PAD, and encompasses smoking cessation, a healthy diet, structured exercise, careful foot monitoring, and adherence to routine preventive treatments such as statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. It is also recommended to incorporate glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in the medical management of patients with T2DM and PAD, due to their demonstrated cardiovascular benefits. However, the specific impact of these novel glucose-lowering agents for individuals with PAD remains obscured within the background of cardiovascular outcome trials (CVOTs). In this review article, we distil evidence, through a comprehensive literature search of CVOTs and clinical guidelines, to offer key directions for the optimal medical management of individuals with T2DM and lower extremity PAD in the era of GLP-1RA and SGLT2i.

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

Cited by 5 publications

References 34 publications

Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease

Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease

GLP-1 receptor agonists’ impact on cardio-renal outcomes and mortality in T2D with acute kidney disease

Challenges and opportunities in the management of type 2 diabetes in patients with lower extremity peripheral artery disease: a tailored diagnosis and treatment review

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