Semaglutide: A New Medical Swiss Army Knife?

Semaglutide and other glucagon like peptide 1 (GLP-1) agonists are commonly prescribed for patients with type II diabetes. In addition to improving patients' blood sugar, it has also demonstrated decreased major cardiovascular events like myocardial infarction and cerebral vascular accident in patients with type II diabetes. Perhaps its most popular effect is weight loss, although it is not marketed as a weight loss drug. A recent article published by Kosiborod et al. (1) evaluated the effect of semaglutide in patients with heart failure with preserved ejection fraction (HFpEF) and obesity, but without diabetes. There have been few effective pharmacologic interventions for patients with HFpEF, and this study will likely increase the number of patients presenting to surgery who are taking semaglutide. Early studies of heart failure (HF) demonstrated no correlation between ejection fraction (EF) and New York Heart Association (NYHA) functional class indicating that systolic dysfunction is not the main cause of HF symptoms (2). It is now clear that more than half of patients with HF have preserved or only mildly reduced EF and develop heart failure due to diastolic dysfunction. This proportion dramatically increases in older population with HF with as much as ¾ of patients over 65 having HFpEF. The American College of Cardiology Foundation and the American Heart Association define heart failure with preserved ejection fraction as patient having heart failure symptoms while having LVEF greater than 50% and evidence of LV diastolic dysfunction. The proportion of HFpEF patients has steadily increased over last three decades driven by the aging population. The aging process in combination with physical inactivity, obesity, hypertension and diabetes all contribute to worsening or accelerating a natural decline in LV compliance. The pathogenesis of HFpEF involves a complex mechanism that result in increase in myocardial stiffness that is a result of both cellular and molecular mechanisms that are the result of alterations in myocyte control of calcium, impaired mitochondrial function, inflammation and increase in collagen in the extracellular matrix (3). HFpEF patients have normal systolic function and impaired diastolic function, but many of them do not demonstrate the abnormal diastolic function on echocardiograms performed at rest and the abnormality can be only uncovered during exercise testing. Since perioperative assessment of our patients depends mostly on resting echocardiograms, many patients who have diastolic functions are not diagnosed as such. We as anesthesiologists have special interest in this population because of the exquisite sensitivity of these patients to changes in preload and afterload that are regular occurrences during perioperative period. Unfortunately, most of the perioperative studies have shown no morbidity or mortality benefits or reduction of hospitalization for heart failure by many interventions including ace inhibitors, angiotensin receptor blockers, beta blockers, digoxin, sildenafil, nitrates, ivabradine, neprilysin inhibitors, soluble guanylate cyclase stimulators and other medications (4). Therefore, at present we do not have effective treatment for patients with heart failure with HFpEF or interventions that would reduce risks or improve care and outcomes in perioperative period. Multiple studies have shown that patients with HFpEF undergoing cardiac surgery have a greater risk of mortality, an increased risk of cardiogenic shock as well as a higher incidence of perioperative kidney injury than patient without HFpEF. The excess mortality in patients with HFpEF persist even after CABG surgery and is fourfold higher than patients with preserved ejection fraction without heart failure and also significantly higher than patients with reduced EF but without HF (5). The outcomes in women were worse than those for men. Several studies investigating effects of HFpEF on outcomes after non-cardiac surgery also demonstrated adverse effect of heart failure with preserved ejection fraction on hospital stay readmissions and increased incidence of major adverse cardiovascular and cerebral vascular events after non-cardiac surgery (6). These outcome studies highlight the importance of exercise capacity and a history of heart failure with adverse events in perioperative period. GLP-1 is a hormone that is released in the gastrointestinal tract in response to eating. The main effect of GLP-1 is an increased production and secretion of insulin, a decrease in liver glucose production and a reduction in gastric emptying. GLP-1 also interacts with the brain that produces a feeling of fullness, reduction of appetite, reduced blood glucose level and eventually weight loss. In addition, GLP-1 produces many other effects (7) as summarized in table 1.Table 1Effects of the Glucagon like peptide – 1 (GLP-1).GI tractBrainLiverPancreasKidneyHeart↓Gastric emptying↓Appetite↓Glucose production↑Insulin production↑Natriuresis↓Blood pressure↓Acid Production↑ Satiety↓Fat content↑Insulin secretion↑ Diuresis↓Heart Rate↓GI motility↑Energy expenditure↓Plasma liver enzymes↓Glucagon secretion↑Contractility↑Neuroprotection↑Beta cell proliferation↑Cardio protection↓Neuroinflammation↑Beta cell survival↓Inflammation↑Memory and learning↓Blood glucose↓Ischemic injury↑Stem cells↓Apoptosis↓Natriuretic peptide secretion Open table in a new tab Table 2Effects of Semaglutide and placebo on primary and secondary endpointsEND POINTSemaglutide (N=263)Placebo(N=266)P valuePrimary end pointsChange in KCCQ-CSS16.68.7<0.001% change in BW-13.3-2.6<0.001Confirmatory secondary end pointsChange in 6-minutes walk distance (m)21.51.2<0.001Change in CRP level (%)-43.5-7.3<0.001Composite end point (% wins)60.134.9<0.001Percent reduction in BW>10 %65.99.5>15 %43.92.1>20 %23.60.4% reduction in NT-proBNPs-20.9-5.3Adjudicated heart failure events (n)112 Open table in a new tab Semaglutide is one of many FDA-approved GLP-1 receptor agonists that mimic GLP-1 actions but have much longer half-life. Semaglutide was the seventh GLP-1 agonist approved by FDA (2018) for the treatment of Type 2 diabetes and obesity and now is marketed by Novo Nordisk as 3 different preparations including two injectable forms and one tablet form. Semaglutide is an analogue of liraglutide that is chemically modified to extend the half-life to 160 hours after subcutaneous injection in humans allowing convenient once weekly administration. In a study of semaglutide in patients with HFpEF and obesity Kosiborod et al. randomly assigned 529 patients with HFpEF and body mass index of 30 or higher to receive either once weekly injection of semaglutide at the maximum weekly dose of 2.4 mg or placebo for 52 weeks. The study enrolled patient at 96 sites in 13 countries across four continents. The vast majority of patients enrolled in the study were white (95.8%) despite the fact that 23.2% of participant enrolled in the United States were black. The patients that were enrolled in the study had preserved EF of at least 45% (median EF of 57%) and a body mass index of at least 30 with NYHA York functional class two (66.2 %), and a six-minute walk test of at least 100 meters. Patients also had to have at least one of the following findings: elevated cardiac filling pressures, an elevated proBNP level plus echocardiographic abnormalities or with hospitalization for HF in the preceding 12 months. The majority of the patients (72%) qualified for the study based on proBNP levels in combination with echocardiographic abnormalities. Table two summarizes main finding of the study for semaglutide and placebo groups. Patients in the semaglutide group had greater improvement in KCCQ-CSS score (greater reduction in symptoms and physical limitations) and a 13% reduction in body weight and both of these primary end points were highly statistically significant (p<0.001). Over 23% patient in the semaglutide group experienced more than a 20% reduction in body weight. There was also significant improvement in 6-minute walk distance and a 43.5% reduction in CRP level in semaglutide group. The medication was extremely well tolerated and only 35 patients (13.3%) reported serious adverse events which was less than half of 71 serious adverse events reported in control group participants (26.7%) (P<0.001). Patients in the semaglutide group had fewer cardiac adverse events (7) that included atrial fibrillation, atrial flutter and congestive cardiac failure than control group (30) (p<0.001). That group also had a significantly smaller number of infections (p<0.006) and dramatically reduced incidence of respiratory, thoracic or mediastinal events (p<0.002). GLP-1 agonists are known to increase risk of gastrointestinal complications including pancreatitis, bowel obstruction and gastroparesis (8). In this study it appears that these disorders were not severe and serious gastrointestinal disorders affected only one patient in each group. Based on this and other studies, we know that patients with HFpEF are very symptomatic and have poor quality of life. Patients value a reduction of symptoms and an ability to increase physical activity. Many studies using a variety of pharmacological agents have failed to show benefits in this population (4). This study is promising for our HFpEF patients, but it raises many questions. What part of the beneficial effects is due to weight-loss and what part is due to a direct effect on the heart and reduction of generalized inflammation? We hope that further studies will be able to delineate the importance of these factors in the beneficial effects of semaglutide. While we all are excited about the positive effects of semaglutide demonstrated by this study, there are also potential problems with this medication class in the perioperative period. The ASA recently published recommendations on patients taking semaglutide. While there are not robust studies identifying the perioperative effects, there are case reports identifying an increased risk of aspiration during anesthesia for patients on these medications. The ASA recommends holding these medications for a week for patients taking the medications weekly. There are still many unanswered questions with regards to semaglutide, but it is likely that more studies will be published in the near future that will only increase its popularity. 1)Kosiborod MN, Abildstrøm SZ, Borlaug BA et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023; 389:1069-10842)Dougherty AH, Naccarelli GV, Gray EL et al. Congestive heart failure with normal systolic function. Am J Cardiol. 1984; 54:778-823)Bradshaw AD, DeLeon-Pennel and DR Menick. Molecular, Gene, and Cellular Mechanism. 2021; in Klein AL and Garcia MJ. Diastology, Clinical Approach to heart failure with preserved ejection fraction 2nd edition Elsevier, Philadelphia PA4)Pagel PS, Tawil JN, Boettcher BT et al. Heart Failure with Preserved Ejection Fraction: A Comprehensive Review and Update of Diagnosis, Pathophysiology, Treatment, and Perioperative Implications. J Cardiothorac Vasc Anesth. 2021; 35:1839-18595)Sun LY, Tu JV, Eddeen AB, Liu PP. Prevalence and Long-Term Survival After Coronary Artery Bypass Grafting in Women and Men with Heart Failure and Preserved Versus Reduced Ejection Fraction. J Am Heart Assoc. 2018; 7: e0089026)Mohananey D, Heidari-Bateni G, Villablanca PA et al. Heart failure with preserved ejection fraction—a systematic review and analysis of perioperative outcomes. J Cardiothorac and Vasc Anesth. 2018; 32:2423-24347)Müller TD, Finan B, Bloom SR et al. Glucagon-like peptide 1 (GLP-1). Molecular Metabolism. 2019; 30: 72-1308)Sodhi M, Rezaeianzadeh R, Kezouh A et al. Risk of Gastrointestinal Adverse Events Associated with Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. 2023; 330:1795–1797 Jure Marijic: Conceptualization, Methodology, Writing – original draft. J. Prince Neelankavil: . We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We know of no conflicts of interest associated with this publication, and there has been no significant financial support for this work.