Exploring the clinical effectiveness of Glucagon Like Peptide 1 receptor agonists in managing cardiovascular complications: an updated comprehensive review and future directives

Joshi, Nandan MBBSa; Qasim, Muhammad Zohaib MBBSb; Kanumilli, Srilakshmidevi MBBSc; Shaukat, Faiza MBBSd; Kumar, Ateesh MBBSe; Mahek, Fnu MBBSf; Khalid, Saif MBBSg; Zeeshan, Mohd MBBSh; Shaik, Mahboob Younus MBBSi; Nishat, Syeed Mahmud MBBSj,*;Gandhi, Fenil MD, MHAk; Belletieri, Christopher DOl.

Please note that this submission comes from a resident at Lower Bucks Hospital and has been copied from the Annals of Medicine and Surgery website. You can find the orginal text through the provided link. Lower Bucks Hospital does not own the rights to this publication.

https://journals.lww.com/annals-of-medicine-and-surgery/fulltext/2024/10000/exploring_the_clinical_effectiveness_of.38.aspx

Abstract

The possible cardiovascular advantages of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), a class of drugs predominantly used to treat type 2 diabetes (T2D), have garnered increasing attention in recent years. Clinical trials have looked into the possibility that GLP-1RAs have extra cardioprotective benefits in addition to their ability to manage T2D, demonstrating significant major adverse cardiovascular events (MACE) reduction and a favorable safety profile. GLP-1 RAs improve cardiovascular outcomes, especially in those with existing cardiovascular disease. MACE has been steadily declining with this class of drugs, which results in a noticeable rise in cardiovascular outcome trials (CVOTs). GLP-1 RAs have a variety of impacts on the cardiovascular system beyond their function in glycemic control. They offer direct cardioprotection, vasodilation, promotion of salt excretion, reduction of weight, improved lipid profile, and anti-inflammatory qualities through a variety of mechanisms. Thus, this review focuses on GLP-1RAs, its mechanism of action, its clinical effectiveness in CVOTs, the mechanism behind its cardiovascular benefits, its potential role in heart failure, cardiovascular outcomes, its underutilization, and future directives. In conclusion, GLP-1 RAs shows potential in controlling T2D while also lowering cardiovascular risk, but warrants further study into long-term results and real-world data to optimize treatment regimens, ultimately increasing patient outcomes and lowering the burden of cardiovascular disease in T2D populations.

Highlights:

• Individuals with type 2 diabetes (T2D) face a three-fold higher risk of mortality from coronary artery disease compared to those without diabetes, resulting in significant reductions in life expectancy.
• In T2D patients, cardiovascular outcome trials (CVOTs) have shown that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events (MACE), cardiovascular mortality, non-fatal myocardial infarction (MI), and non-fatal stroke rates.
• GLP-1 RAs exert antihyperglycemic effects by reducing food intake, delaying gastric emptying, inhibiting glucagon secretion, and enhancing glucose-dependent insulin release. They also have weight-reducing and hypoglycemia-lowering properties.
• GLP-1 RAs offer potential for managing heart failure (HF) by various means, including direct heart protection, promotion of natriuresis and vasodilation, and control of weight and glucose levels.
• GLP1-RAs have been recommended by the American College of Cardiology (ACC), the European Society of Cardiology (ESC), and the American Diabetes Association (ADA) for use in treatment regimens aimed at reducing atherosclerotic cardiovascular disease (ASCVD) in high-risk patients with T2D.

Cardiovascular complications dominate the landscape of type 2 diabetes (T2D) as the primary reason for both mortality and morbidity^1,2, and individuals with diabetes exhibit an approximately three-fold increase in mortality rate due to coronary artery disease compared to non-diabetic individuals³. For individuals 50 and older with diabetes, there is a considerable differential in life expectancy without cardiovascular disease: women face a 7.8-year decline, while men face a slightly larger decrease of 8.4 years⁴. When combined, diabetes and atherosclerotic cardiovascular disease (ASCVD) increase mortality and reduce life expectancy by 12-15 years⁵. Improvements in diabetes therapy options and the subsequent publication of cardiovascular outcomes trials (CVOTs) for newer antihyperglycemic drugs have led to modifications in treatment algorithms for people with T2D. According to current guidelines, physicians should prioritize lowering cardiovascular risk by using a cardiometabolic approach rather than a glucocentric one^6-10.

As part of the endeavor to assess cardiovascular health and the efficacy of various anti-diabetic medications, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have drawn a lot of interest, which has resulted in a noticeable rise in CVOTs during the last 10 years. Since major adverse cardiovascular events (MACE) have been steadily declining with this class of drugs, CVOTs have expressed a significant interest in them. This holds particularly true for non-fatal stroke rates, cardiovascular mortality, and non-fatal myocardial infarction (MI) incidence. Numerous pathways contribute to these favorable results for cardiovascular outcomes¹¹. Additionally, it has been established that selective GLP-1 RA, dulaglutide, liraglutide, injectable, and oral semaglutide delay the progression of macroalbuminuria and are beneficial for atherosclerotic cardiovascular disease (ASCVD) in both primary⁵ and secondary preventive groups⁶. Because of this, the American Diabetes Association (ADA) now suggests, without regard to baseline A1C, customized A1C target, or metformin usage, these particular GLP-1 RA as first-line treatment in those with T2D and ASCVD or those with symptoms of high cardiovascular risk. Unless there are contraindications, GLP-1 RAs should also be taken into consideration as the first injectable treatment for those with T2D, independent of cardiovascular risk¹². This comprehensive review explores the clinical effectiveness of GLP-1RAs with an emphasis on cardiovascular outcomes, offering a thorough and current overview along with recommendations for future research.

Mechanism of action of glucagon-like peptide-1 receptor agonists

GLP-1RAs are synthetic analogs of the gut hormone GLP-1, which increases the pancreatic release of insulin, a process known as the incretin effect that decreases blood glucose levels. Unlike the natural hormone, these synthetic GLP-1RAs are resistant to degradation by the body enzyme dipeptidyl peptidase 4 (DPP-4), which prolongs the duration of activity. GLP-1 has also been shown to have limited activity in T2D patients. By promoting the growth of beta cells in the pancreas and enhancing satiety, GLP-1 RAs decrease appetite and the rate of gastric emptying. Additional studies show that GLP-1 RAs aid in the restoration of insulin secretory activity, which benefits diabetic patients by improving glycemic control and promoting weight reduction. While long-acting formulations impact both fasting and postprandial glucose levels, short-acting GLP-1RAs largely lower postprandial glucose concentration by delaying gastric emptying. Clinical evidence indicates that GLP-1 analogs may have additional beneficial effects on various body receptors, such as lowering blood pressure, enhancing myocardial and endothelial tissue function, assisting failing or ischemic heart tissue in recovering, promoting arterial vasodilatation, and bolstering natriuresis and diuresis¹³.

Oral vs. injectable glucagon-like peptide-1 receptor agonists

In individuals with T2D inadequately managed on basal insulin, a network meta-analysis comparing once-daily oral semaglutide to injectable GLP-1 RAs consisted of seven trials. The results showed that, in contrast to most other GLP-1 RA therapies, the HbA1c levels fell quickly with once-daily oral semaglutide 14 mg, decreasing between −0.42% and −1.32%. The 0.5 or 1 mg injectable semaglutide administered once a week did not show any statistically significant difference from the 14 mg oral semaglutide administered once a day. Weight reductions with once-daily oral semaglutide 14 mg were significantly greater than those with exenatide 2 mg and lixisenatide 20 μg, varying by −2.21 and −2.39 kg, respectively. Once-daily oral semaglutide 14 mg was shown to be more effective in reducing weight than most other therapies, except for once-weekly injectable semaglutide 1 mg, even though the difference was not statistically significant. Comparable trends were seen by the composite endpoint and those with HbA1c levels of less than 6.5% and less than 7.0%. The incidence of nausea, vomiting, or diarrhea with oral semaglutide 14 mg once a day was similar to all other GLP-1 RA therapies. The results show that 14 mg of oral semaglutide added to basal insulin once daily can considerably decrease body weight and HbA1c, enabling the accomplishment of glycemic control throughout a 26 ± 4 week period. The oral semaglutide 14 mg has equivalent or higher effectiveness and a good tolerability profile when compared to the majority of injectable GLP-1 RAs¹⁴.

Contraindications on glucagon-like peptide-1 receptor agonists use

A warning about GLP-1 receptor agonist contraindications is as follows:

• It is contraindicated to provide any GLP-1 RA to someone who has a known GLP-1 RA drug hypersensitivity^15,16.
• There is a higher chance of deadly hemorrhagic and necrotizing pancreatitis with any GLP-1 analog. Although post-marketing surveillance has identified this, the precise mechanism causing pancreatitis is unknown. If a patient has a history of pancreatitis or develops pancreatitis, GLP-1 RAs should be stopped¹⁷.
• Patients with a family history of medullary thyroid cancer or those with type 2 multiple endocrine neoplasia are not candidates for semaglutide, dulaglutide, exenatide extended-release, liraglutide, or tirzepatide. Liraglutide was found to cause C-cell hyperplasia and raise calcitonin release in rats. For conclusive results on people, more research is needed^18,19.
• Patients with end-stage renal disease and a CrCl less than 30 ml/min should not use exenatide. Additionally, if a complete blood count panel confirms that exenatide is causing drug-induced thrombocytopenia, the medication should be stopped right away.
• GLP-1RAs should not be used in people who have a history of inflammatory bowel disease or gastroparesis. They should also be taken cautiously by women who are pregnant. Research on animals has demonstrated that at dosages greater than the maximum advised human dosage, teratogenicity, intrauterine mortality, and adverse effects on embryo-fetal development can occur. There is not enough evidence available on drug-associated risk for other GLP-1RAs. Consequently, these drugs ought to be administered only in cases when the mother's possible benefit outweighs the fetus's possible danger.
• Regarding compounded semaglutide formulations, the FDA issued a warning. Patients and medical professionals are being reminded by the FDA that compounded medications are not FDA-approved. The safety and efficacy of compounded drugs have not been assessed by the FDA. Semaglutide compounded with different salts has been associated with serious side effects. The FDA has been notified of three linked recent reports of patient injury resulting from adult users of semaglutide at dosages meant to produce weight reduction. Semaglutide is authorized for the treatment of diabetes. People got the drug from spas and compounding pharmacies. After taking a dosage that exceeded the prescribed amount by 10 times, two individuals had extreme stomach discomfort, nausea, and vomiting. One of them had an overdose that needed medical attention, but it was resolved with treatment. Patients were given syringes to self-administer without receiving the appropriate instruction on how to use them. Overdose might be lethal in this case since the compounded semaglutide lacks safety mechanisms. Dosing variations and confusion might be caused by using the incorrect syringes. Strict labeling, dispensing, and counseling procedures are necessary to reduce the risks. To prevent serious adverse effects and hospitalizations due to dosage mistakes, healthcare providers should promote its correct usage²⁰.
• The FDA has also issued a warning on semaglutide-related ileus. According to recent research, compared to bupropion-naltrexone, using GLP-1RAs for weight reduction carries a greater risk of pancreatitis, gastroparesis, and intestinal obstruction^21,22.

Evaluating cardiovascular outcome trials for glucagon-like peptide-1 receptor agonists

CVOTs have become essential in evaluating the cardiovascular effects of GLP-1 RAs²³. The GLP-1 RA family of anti-diabetic medications has garnered significant interest because of its capacity to control blood sugar levels and its advantages for CVS²⁴. Since regulatory agencies demand that anti-diabetic medications not increase the risk of developing cardiovascular disease, CVOTs have become a crucial part of the review process. The goal of these precisely constructed randomized, placebo-controlled studies is to look into the impact of anti-diabetic medicines on cardiovascular events, especially in poorly controlled glycemic control patients²³. By connecting diabetes care with cardiovascular health, CVOT addresses the urgent need to lower cardiovascular events in this susceptible patient group.

The LEADER study, which showed that liraglutide improves cardiovascular outcomes in people with T2D and elevated cardiovascular risk, was a critical turning point. Participants in the trial were given a daily dosage of 1.8 mg of liraglutide and had a median age of 64 years, an A1C level of 8.7%, and an average duration of 12.8 years with diabetes. There were over 9340 people with T2D in total. Remarkably, 81% of participants had CVD at the time of registration. In contrast to trials like ELIXA and EXSCEL, the LEADER study boasted an extended average period of follow-up that was 3.8 years longer. The analysis demonstrated a notable decrease in the composite of MACE with liraglutide compared to placebo [HR: 0.87 (95% CI: 0.78-0.97)]. A significant fall in cardiovascular mortality, as shown by a [HR: 0.78 (95% CI: 0.66-0.93, P=0.007)], was the primary cause of this decline. On the other hand, there was no discernible decline in non-fatal MI or stroke. Fascinatingly, there was no variation in the risk of MACE depending on heart failure (HF) state at baseline in the post hoc analysis, nor was there a significant difference in the incidence of hospitalization for HF among the therapy groups, as indicated by [HR: 0.87 (95% CI, 0.73-1.05, P=0.14)]. Additionally, liraglutide use did not substantially increase the incidence of diabetic retinopathy^25-27.

Many pivotal trials, including SUSTAIN-6, REWIND, and Harmony, have confirmed the effectiveness of weekly injected GLP-1 RAs in improving cardiovascular health. For instance, semaglutide demonstrated a substantial 26% decrease in the incidence of MACE in patients with T2D, mostly as a result of a large 39% decline in non-fatal stroke occurrences as compared to the control group in the SUSTAIN-6 study. While in the REWIND trial, dulaglutide was also found to be superior to a placebo in terms of lowering the incidence of non-fatal strokes. Notably, there was no appreciable variation in the risks of non-fatal MI or cardiovascular death between individuals in the SUSTAIN-6 and REWIND trials who received GLP-1 RAs and those who received placebos. In contrast, the Harmony Outcomes trial identified ASCVD and specifically targeted T2D patients. Albiglutide, as opposed to a placebo, significantly decreased MACE in this high-risk population. Remarkably, in contrast to semaglutide, albiglutide significantly reduced the incidence of MI in SUSTAIN-6^28-30. Since 4076 high-risk patients in the AMPLITUDE-O trial had at least one cardiovascular risk factor and pre-existing renal or cardiovascular illnesses, they were treated with efpeglenatide, a weekly injectable GLP-1 RA. According to the trial findings, a possible relationship between dosage and the incidence of MACE was seen in the AMPLITUDE-O trial; the hazard ratio between the 6 mg per week dosage of efpeglenatide and placebo was 0.65 (95% CI: 0.5-0.86). The hazard ratio for the weekly dosage of 4 mg was 0.82 (95% CI: 0.63-1.06)³¹. With the exception of the REWID study, the majority of patients in the preceding studies had previous cardiovascular problems, confirming the efficacy of GLP-1 RAs in secondary prevention. Due to the limited proportion of patients with previous cardiovascular illness in the REWIND trial (31%), dulaglutide's effectiveness in preventive care was proven. In the ELIXA and EXSCEL trials, whether lixisenatide was given once daily or once weekly, respectively, there was no statistically significant reduction in MACE when compared to placebo. However, they were judged to be non-inferior to placebos in relation to the primary combined outcome of MACE. Although the MACE did not decrease in participants receiving lixisenatide compared to those receiving a placebo, the ELIXA trial emphasized the assessment of cardiovascular well-being associated with lixisenatide in this particular at-risk group as the trial focused on patients with recent cardiovascular events, specifically those who had acute coronary syndrome within 180 days prior to randomization^32,33. Cardiovascular outcome trials for glucagon-like peptide-1 receptor agonists are summarized in Table 1.

The PIONEER 6 trial introduced an innovative oral form of GLP-1 RA. Even though the trial was published in 2019, it did not seem to be better at lowering MACE but provided insightful information about the oral administration and safety of GLP-1 RAs, increasing the range of available treatments for T2D patients³⁴. The potential cardiovascular advantages of oral semaglutide in individuals with T2D, pre-existing ASCVD, and/or CKD are now being investigated by the Semaglutide Cardiovascular Outcomes (SOUL) study³⁵. In comparison to a placebo and 0.9 mg liraglutide, the Japanese PIONEER 9 study demonstrated the subtle benefits of oral semaglutide by showing substantial decreases in both HbA1c levels and weight loss³⁶. Comparably, a significant increase is indicated by raising the dulaglutide dosage from 1.5 mg in those with unsatisfactorily metformin-controlled T2D to either 3 mg or 4.5 mg, which led to improvements in HbA1c and weight reduction that were dose-dependent while also keeping the same safety profile in the AWARD-11 Randomized Control Trial³⁷. While a number of CVOTs only addressed target dosages without exploring dose-dependent analyses, their collective contributions greatly improved our comprehension of the cardiovascular effects of GLP-1 RAs in T2D. These collective insights have improved therapeutic approaches, enabling medical professionals to customize care to each patient's unique requirements.

Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. https://journals.lww.com/annals-of-medicine-and-surgery/fulltext/2024/10000/exploring_the_clinical_effectiveness_of.38.aspx

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