The SUSTAIN-6 trial provided compelling evidence for the cardiovascular benefits of semaglutide, demonstrating a 26% reduction in the risk of major adverse cardiovascular events in T2DM patients with elevated cardiovascular risk .
Semaglutide, a GLP-1 receptor agonist, has demonstrated superior cardioprotection for people with T2DM compared to other treatments. Clinical trials like SUSTAIN and PIONEER found that it reduced major adverse cardiovascular events (MACE) by approximately 26%, outperforming other diabetes drugs . Its benefits extend beyond glycemic control, including weight reduction and anti-inflammatory effects, which collectively lower cardiovascular risks. These advantages make semaglutide especially effective for T2DM patients with pre-existing cardiovascular conditions.
Additionally, patients with Heart Failure With Preserved Ejection Fraction (HFpEF) and obesity, semaglutide produced large improvements in HFpEF related symptoms . HFpEF is when the ventricles of the heart are unable to fill or eject blood as they should. Thus, patients suffer from dyspnea, fatigue, congestion and heart failure (HF) . Using mouse models, Withaar et al. came the same conclusion, finding that semaglutide treatment significantly reduced messenger RNA levels of cardiac stretch marker and inflammatory markers like interleukin-6, which is consistent with functional improvements. Semaglutide treatment is also found to decrease myocardial diastolic stiffness and improve actin-myosin and muscle contraction pathways. There must be a pathway where semaglutide are able to exert anti-inflammatory effects, which should be the focus of more studies.
Semaglutide therapy also reduced incidence of any stroke when compared to a placebo through significant reductions in risk of small-vessel occlusion in a post hoc analysis of the SUSTAIN 6 and PIONEER 6 trials In addition, Avgerinos et al. , conducted a meta-analysis and concluded that semaglutide therapy was associated with a 39% decrease In the risk of ischemic stroke . Semaglutide therapy also seems to decrease incidence of stroke comparative to other therapies, specifically a dipeptidyl peptidase-4 inhibitor . While there have been studies on the incidence of stroke in patients on semaglutide compared to a specific T2DM therapy, there is a need to understand how T2DM therapies generally compare to each other in reducing risk of stroke.
Maskery et al. conducted a systematic review confirming previous studies findings that semaglutide therapy is associated with decreased incidences of stroke. The study also concluded semaglutide therapy was associated with reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow.
Semaglutide therapy has also garnered attention for its potential therapeutic effects for Alzheimer’s Disease. Alzheimer’s Disease is a neurodegenerative disease characterized by dementia and cognitive impairment in language, comprehension, memory and more . Specifically, semaglutide therapy has been associated with associated with decreased amyloid-beta plaque deposition and neuroinflammation. It’s effects on the central and peripheral nervous system are thought to mediate these effects, party through ability to cross the blood-brain barrier. While the specific mechanism of action is unknown, it is thought that since neurons rely on consistent regulation of glucose transporters to prevent neurodegeneration, a pathway that semaglutide therapy directly modulate, it is able to exhibit pleiotropic effects . Pooled data from three randomized controlled trails and a nationwide registry-based cohort have consistent findings. Nørgaard et al. found that rates of dementia were lower in patients undergoing G1PR agonists compared to a placebo in both the randomized control trail patient data and nationwide cohort data . There is a need for more studies to explore the idea of repurposing semaglutide therapy for Alzheimer’s Disease treatment.
One of the main goals of semaglutide therapy is a reduction in HbA1c levels to improve glycemic control. Subcutaneous semaglutide, administered once weekly, has shown a 1. 5–1. 8% reduction in HbA1c levels over 30–56 weeks in various SUSTAIN trials. For example, in SUSTAIN 1, subcutaneous semaglutide reduced HbA1c by 1. 6% after 30 weeks, making it superior to several comparators, including sitagliptin, liraglutide, and insulin glargine .
In contrast, oral semaglutide, taken once daily, demonstrated HbA1c reductions ranging from 1. 0–1.4% in the PIONEER trials, achieving a 1.4% reduction after 26 weeks in PIONEER 1 . Although effective, this was slightly less potent compared to subcutaneous semaglutide. Nevertheless, oral semaglutide achieved similar efficacy to liraglutide and better outcomes than sitagliptin or empagliflozin. A PIONEER REAL pooled analysis also indicated that individuals on oral semaglutide treatment experience better glycemic control and weight loss across various age groups and durations of T2DM .
The differences in glycemic control between the two formulations may be influenced by the consistency of plasma concentration, with subcutaneous administration yielding a more stable pharmacokinetic profile.
Recent studies have also looked at new mechanisms of action utilizing semaglutide. Schneider et al. 2024 looked into possible mechanisms for a long-acting version of the semaglutide. Semaglutide was attached to hydrogel microspheres with a cleavable linker, designed for release over about one month. In mice, a single subcutaneous dose showed a release half-life of approximately 36 days, leading to a 20% weight loss over one month, similar to twice daily semaglutide doses Simulations suggested that this microsphere formulation could allow for once-monthly human dosing while maintaining effective drug levels, potentially reducing adverse side effects.
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