Effect of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists on Subclinical Atherosclerosis in Non-diabetic Patients With Psoriatic Arthritis - a Proof-of-concept Randomized Study
Effect of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists on Subclinical Atherosclerosis in Non-diabetic Patients With Psoriatic Arthritis - a Proof-of-concept Randomized Study
Background Psoriatic arthritis (PsA) patients are at increased risk of cardiovascular disease. Glucagon-Like Peptide-1 (GLP-1) receptor agonists are cardiovascular protective in diabetics. They have also anti-inflammatory properties. It is hypothesized GLP-1 receptor agonists can prevent the progression of atherosclerosis due to the combination of metabolic factors and disease activity control in non-diabetic PsA patients.
Objectives To investigate the vascular effects of GLP-1 receptor agonists in PsA patients without diabetes. Their metabolic and anti-inflammatory roles will also be examined.
Design and subjects This is a pilot randomized open-labelled trial. We plan to enroll 40 non-diabetic patients with PsA. Participants will be randomized 1:1 to either GLP-1 receptor agonist (semaglutide) or control group.
Study instruments Subclinical carotid artherosclerosis is assessed by high-resolution ultrasound. Arterial stiffness is measured using pulse wave velocity by a tonometry system, and augmentation index by the SphygmoCor device. These assessments will be done at baseline and 24 weeks. Drug adversities will also be documented. Anthropometric measurements, sugar metabolism and lipid levels as well as the PsA disease activity will be monitored.
Psoriatic arthritis (PsA) is associated with an elevated risk of cardiovascular disease (CVD), which contributes to significant morbidity and mortality. A pooled analysis of 11 studies showed that comparing with the general population, there was a 43% higher risk of cardiovascular (CV) event. PsA increases the susceptibility to atherosclerosis through chronic inflammation, high prevalence of traditional CV risk factors, and the impact of medications. Therefore, there is a possibility that suppression of underlying inflammation, combined with effective control of CV risk factors, could potentially disrupt the accelerated development of atherosclerosis and subsequently improve the CV outcomes of patients with PsA.
Glucagon-like peptide-1 receptor agonists (GLP-1) receptor agonists are a new class of antidiabetic medications. Their beneficial effects on CV endpoints in diabetes mellitus (DM) are well-proven. GLP-1 receptor agonists were also reported to reduce the progression of carotid intima-media thickness (CIMT) independently of its effect on glucose control after 8 months in patients with DM. However, their effects on CV outcomes in patients with non-DM remain uncertain. The initial SCALE group of trials studied GLP-1 receptor agonists in non-diabetic patients with higher body mass index (BMI) and found promising results in terms of reducing body weight, blood pressure, and hemoglobin A1c (HbA1c). The SELECT study, a recent landmark large randomized controlled trial, revealed the addition of semaglutide, a long-acting analogue of GLP-1, to standard care was superior to placebo in reducing the risk of major adverse CV events among overweight patients with preexisting CVD who were non-diabetic.
On top of being CV protective, the potential anti-inflammatory properties of GLP-1 receptor agonists make them appealing treatment option for patients with inflammatory arthritis. GLP-1 receptor agonists inhibit lipopolysaccharide-induced inflammation by phosphorylating AMP-activated protein kinase, which leads to the inhibition of the nuclear factor kappa B (NF-κB) pathway. This inhibition is associated with a decrease in the expression of proinflammatory genes responsible for producing various cytokines such as tumor necrosis factor-α and Interleukin-6 that play important roles in the pathogenesis of arthritis. Additionally, GLP-1 receptor agonists have been found to prevent phosphorylation of IκBα, a key inhibitory protein that normally prevents nuclear translocation of NF-κB transcription factors responsible for downstream proinflammatory cytokine production.
Obesity is a pro-inflammatory state which is prevalent in PsA. Weight loss is associated with improved disease activity in PsO and PsA. A recent meta-analysis showed that compared with the control group, lifestyle interventions involving weight loss significantly improved the mean change of Psoriasis Area and Severity Index (PASI) in psoriasis. The CV protective and therapeutic effects of GLP-1 receptor agonists in PsA have not been studied. There is a small observational study involving patients with rheumatoid arthritis (RA) (n=11) and PsA (n=4), which showed an improvement after GLP-1 receptor agonists treatment in disease activity score 28-joint from 4.2 to 2.7 among the responders.
Carotid ultrasound is a noninvasive imaging technique that can identify the presence of carotid plaque and increased CIMT, representing an unequivocal manifestation of atherosclerosis and serving as a surrogate for CVD. We have shown that subclinical carotid atherosclerosis (SCA) was more prevalent in PsA than controls, even without CV risk factors. In PsA, the presence of SCA is linked to a higher risk of future CV events. Moreover, arterial stiffness also serves as a surrogate marker for CV risk. Each 1.0 m/s increase in brachial-ankle pulse wave velocity (ba-PWV) was reported to associate with a 12% rise in the occurrence of total CV events after adjusting for traditional risk factors.
In light of the potential multitude anti-atherosclerosis effects of GLP-1 receptor agonists, we would like to conduct the first interventional study evaluating the efficacy of semaglutide as disease modifying therapy in atherosclerosis in non-diabetic patients with PsA. Two established surrogate markers for CVD will be used. The results of the study will contribute preliminary data and mechanistic insights regarding the possible effects of GLP-1 receptor agonists on arterial wall, atherosclerotic plaques, and PsA disease activity. Promising results will prompt a properly designed study with adequate power to assess the multidimensional efficacy of GLP-1 receptor agonists in patients with PsA that could reshape the future management of PsA patients in terms of CV risk prevention.
Inclusion Criteria:
Exclusion Criteria: