Evaluating the Effects of Glucagon-Like Peptide 1 Receptor Agonists as a Secondary Prevention in Peripheral Arterial Disease: A Meta-Analysis.

Background: Peripheral arterial disease (PAD) is associated with an increased risk of major adverse cardiovascular and limb events. However, the factors influencing major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with PAD remain unclear. Additionally, while some predictive models for MACE and MALE in patients with PAD have been developed, their performance is uncertain. This systematic review aims to identify the factors influencing MACE and MALE in patients with PAD and to systematically evaluate existing predictive models. Materials and methods: We conducted a literature search in PubMed, Embase, and the Cochrane Library to identify studies exploring risk factors for MACE and MALE, as well as predictive models for these outcomes. Data extraction focused on study design, patient demographics, reported influencing factors (e.g., clinical, biochemical), and characteristics of predictive models (e.g., variables, validation methods, performance metrics). We specifically evaluated the methodological quality and risk of bias of the identified predictive models using established tools such as PROBAST (Prediction model Risk Of Bias ASsessment Tool). This study aimed to synthesize evidence on determinants of MACE and MALE and critically appraise existing prediction models to inform future research and clinical decision-making. Results: One hundred and sixteen studies reported factors influencing MACE in patients with PAD. Six studies developed or validated predictive models. Three models were rated as having low risk of bias across all domains, while the other three had unclear or high risk of bias in at least one domain. A total of 118 influencing factors associated with MACE were identified. Common factors included: demographic characteristics (age, smoking); (2) comorbidities (diabetes mellitus (DM), coronary artery disease (CAD), prior stroke, heart failure); (3) clinical measures (body mass index (BMI), systolic blood pressure (SBP)); (4) diagnostic indicators (ankle-brachial index (ABI), estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), serum creatinine); (5) medication use (statins); and (6) classification systems (Rutherford classification, Fontaine classification). Fifty-five studies reported factors influencing MALE in patients with PAD. Six studies developed or validated predictive models. Three models were rated as having low risk of bias across all domains, while the other three had unclear or high risk of bias in at least one domain. A total of 88 influencing factors were identified. Common factors across most studies included demographic characteristics (age, smoking, socioeconomic status), comorbid conditions (DM, chronic kidney disease, hypertension, cerebrovascular disease), clinical factors (degree of frailty, BMI), diagnostic indicators (hemoglobin, serum creatinine, serum albumin), medication use (statin), and other factors (Wound, Ischemia, and foot Infection (WIfI) classification, geriatric nutritional risk index (GNRI)). Conclusions: Building on these findings, we conclude that, although substantial research exists on factors influencing MACE and MALE in patients with PAD, significant variability persists in study design (patient population), external factors (healthcare environment), and research focus. Our review provides a concise yet comprehensive analysis of predictive models for MACE and MALE in patients with PAD, identifies key predictive factors, systematically evaluates these models, and offers recommendations for their improvement.

Glucagon-like peptide-1 receptor agonists are associated with fewer major adverse cardiovascular and limb events in patients with moderate peripheral arterial disease.

DIETARY INTAKE AND CARDIOVASCULAR OUTCOMES IN PATIENTS WITH CHRONIC VASCULAR DISEASE IN THE COMPASS TRIAL

Joint statement from the European Atherosclerosis Society and European Society of Vascular Medicine focuses on patients with peripheral arterial disease

This study aimed to assess the real-world outcomes of people with diabetes mellitus treated with glucagon-like peptide-1 receptor agonists (GLP1RAs) compared with those treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) in terms of major adverse cardiovascular and limb events. Peripheral artery disease is a common cause of morbidity in people with diabetes. Previous cardiovascular outcome trials have demonstrated the benefits of GLP1RAs and SGLT2is for reducing various cardiovascular events, but the safety and efficacy of these drugs on limb outcomes remain subject to debate and ambiguity. A retrospective cohort study was conducted in which data were collected from the Taiwan National Health Insurance Research Database. In total, 379,256 individuals with diabetes receiving either GLP1RA or SGLT2i with treatment initiated between 1 May 2016 and 31 December 2019 were identified. The primary outcome was major adverse limb events (MALE), defined as the composite of newly diagnosed critical limb ischaemia, percutaneous transluminal angioplasty or peripheral bypass for peripheral artery disease, and non-traumatic amputation. The secondary outcome was major adverse cardiac events, which was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke. Other examined outcomes included death from any cause and hospitalisation for heart failure. Propensity score matching was performed at a 1:4 ratio between the GLP1RA and SGLT2i groups to mitigate possible selection bias. A total of 287,091 patients were eligible for analysis, with 81,152 patients treated with SGLT2i and 20,288 patients treated with GLP1RA after matching. The incidence of MALE was significantly lower in the GLP1RA group than in the SGLT2i group (3.6 vs 4.5 events per 1000 person-years; subdistribution HR 0.80; 95% CI 0.67, 0.96), primarily due to a lower incidence of critical limb ischaemia. The reduced risks of MALE associated with GLP1RA use were particularly noticeable in people with diabetic peripheral neuropathy (subdistribution HR 0.66 vs 1.11; p for interaction 0.006). In people with diabetes, GLP1RA use was associated with significantly reduced risks of MALE compared with SGLT2i within the first 2 years after initiation, especially among people with diabetic neuropathy.

GLP-1 Receptor Agonists and Cardiovascular Outcomes in Adults With Diabetes and Peripheral Artery Disease: An Updated Systematic Review and Meta-Analysis.

Percutaneous coronary intervention with peripheral artery disease in the contemporary era: Still life or limb?

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Patients with diabetes and a history of major adverse limb events (MALEs) are at an increased risk of cardiovascular and limb-related complications; however, effective glucose-lowering therapies for secondary prevention in this population are limited. To evaluate whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with reduced risk of MALEs and major adverse cardiovascular events (MACE) compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with diabetes and prior MALEs. This retrospective, nationwide cohort study used data from the Taiwan National Health Insurance Research Database from October 2012 to December 2023. Patients with diabetes and a history of MALE who initiated GLP-1 RAs or DPP-4 inhibitors were included. MALEs were defined as chronic limb-threatening ischemia, lower limb revascularization, or nontraumatic minor and major amputation. Initiation of GLP-1 RAs (liraglutide, dulaglutide, or semaglutide) vs DPP-4 inhibitors. The primary outcome was a composite of lower limb revascularization and nontraumatic major and minor amputation. The secondary outcomes were MACEs (cardiovascular death, ischemic stroke, and myocardial infarction), all-cause mortality, and progression to long-term dialysis. A new-user, active-comparator design with inverse probability of treatment weighting was employed. Among 17 288 patients (mean [SD] age, 70.7 [12.0] years; 10 010 male [57.9%]), 1583 initiated GLP-1 RAs and 15 705 initiated DPP-4 inhibitors. After weighting, the use of GLP-1 RAs was associated with a lower risk of MALEs (subdistribution hazard ratio [SHR], 0.90; 95% CI, 0.83-0.97), primarily due to a marked reduction in amputation (SHR, 0.86; 95% CI, 0.75-0.98). GLP-1 RAs were also associated with reduced risks of MACEs (HR, 0.62; 95% CI, 0.58-0.65), cardiovascular death (HR, 0.57; 95% CI, 0.53-0.61), all-cause mortality (HR 0.63; 95% CI, 0.60-0.66), and progression to dialysis (SHR, 0.61; 95% CI, 0.54-0.70). In this nationwide cohort study of patients with diabetes and prior MALEs, treatment with GLP-1 RAs was associated with significantly lower risks of recurrent limb events, cardiovascular events, all-cause mortality, and kidney disease progression compared with DPP-4 inhibitors. These findings support the preferential use of GLP-1 RAs for secondary prevention in this high-risk population.

AimsPatients with coronary and peripheral artery disease (PAD) have a residual risk of major adverse cardiovascular and limb events despite standards of care. Among patients with coronary artery disease (CAD) and/or PAD selected for low dose rivaroxaban (2.5 mg BID) and aspirin, we sought to determine the highest risk vascular patients. MethodsXATOA is a single-arm registry of CAD and/or PAD patients. All participants were initiated on low dose rivaroxaban (2.5 mg BID) and aspirin. We report the incidence risk of MACE or MALE and major bleeding. A classification and regression tree analysis (CART) determined independent subgroups. ResultsBetween November 2018 and May 2020, 5,808 participants were enrolled in XATOA; 5,532 were included in the full analysis. The median follow-up (interquartile range) was 462 (371-577) days. The incidence risk per 100 pt-years of major adverse cardiovascular events (MACE) or major adverse limb events (MALE) was highest among participants with polyvascular disease (2 or more vascular beds affected, n=2889). The incidence risk was 9.16 versus 2.48 per 100 patient-years in polyvascular and non-polyvascular patients respectively. Other subgroups of high-risk patients included participants 75 years or older, with a history of diabetes, heart failure, or chronic renal insufficiency (CRI). Rates of major bleeding were low overall. A CART analysis showed that polyvascular disease was the most dominant factor separating higher from lower risk participants, and this was heightened with CRI or diabetes. ConclusionPatients with polyvascular disease represent a substantial subset of patients in clinical practice and should be prioritized to receive maximal medical therapy including low dose rivaroxaban (2.5 mg BID) and aspirin. Lay summaryPatients with coronary and peripheral artery disease have a residual risk of major adverse cardiovascular and limb events despite standards of care. In the XATOA registry, we determine the highest risk vascular patients and report the incidence risk of major adverse cardiovascular events, major adverse limb events, and major bleeding.Rates of major bleeding were low overall. Polyvascular disease was the most dominant factor and was heightened with CRI or diabetes.Patients with polyvascular disease should be prioritized to receive maximal medical therapy including low dose rivaroxaban (2.5 mg BID) and aspirin.

Tirzepatide and major adverse limb events: Insights from a multicenter real-world analysis in PAD and diabetes patients.

On the rise but still underutilized - why statins are the Achilles' heel of secondary prevention in peripheral arterial disease.

Racial Disparities in Treatment Indications and Outcomes for Limb Ischemia

Vorapaxar for Prevention of Major Adverse Cardiovascular and Limb Events in Peripheral Artery Disease.

Collectively, coronary artery disease (CAD) and peripheral artery disease (PAD) are highly prevalent and are associated with increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Improved ability to identify those at highest risk of these events may help optimize secondary prevention efforts in this population. Using the Optum Integrated Database, a healthcare claims database linked to electronic medical records (EMR), we identified patients with CAD and/or PAD between January 1, 2009, and September 30, 2016. Index date was the earliest date on which chronic and stable disease was established. Follow-up ran from index date until earliest of patient death, plan disenrollment, or end of study. We developed multivariate Cox proportional hazards models to identify predictors of MACE and/or MALE, limited to measures presumed available to clinicians during patient encounters (e.g., age, presence of selected comorbidities). A total of 20,932 patients met all selection criteria; 86.9% had CAD and 26.1% had PAD; 13% (n = 2753) experienced MACE and/or MALE during a mean follow-up of 2.3years, for a rate of 7.1 events per 100 person-years (PYs). We identified 11 predictors of MACE and/or MALE. Most (95.1%) patients had ≥ 1 predictors; 34.0% and 6.9% had ≥ 4 and ≥ 6, respectively. Incidence of MACE and/or MALE was strongly correlated with number of predictors (r2 = 0.98), ranging from 2.3 per 100 PYs among those without predictors (4.9% of patients) to 18.7 per 100 PYs among those with ≥ 6 (6.9%). Patients with ≥ 1 predictor experienced 7.4 MACE and/or MALE per 100 PYs. Readily identifiable predictors can be used to identify subgroups with chronic CAD and/or PAD at elevated risk of MACE and/or MALE. Further research is required to understand the degree to which these subgroups may benefit from early identification and treatment with secondary prevention therapies. Janssen Pharmaceuticals.