Expanding GLP-1 Receptor Agonist Access: Key Heart Outcomes

In recent years, several new medications for obesity and diabetes have entered the market, promising significant health benefits. While these treatments can help with weight loss and blood sugar control, there is growing scrutiny around their side effects, particularly concerning heart health. Understanding how these drugs interact with cardiovascular risks is crucial for patients, doctors, and healthcare systems.

Why it matters

With obesity and type 2 diabetes rates soaring, these medications could pave the way for improved health outcomes for millions. However, as more options become available, it’s essential to understand the specific advantages and drawbacks of each medication. Recent studies have highlighted differences in how these drugs perform, particularly regarding heart-related events. As federal policies aim to make these treatments more accessible, a clearer picture of their safety can lead to better patient care and outcomes.

Tirzepatide vs Dulaglutide

In a recently published study, researchers did a head-to-head comparison of tirzepatide and dulaglutide in patients with type 2 diabetes with a focus on cardiovascular outcomes (SURPASS-CVOT, NCT04255433). This study was an active comparator–controlled, double-blind, noninferiority trial that began in 2020. Patients with type 2 diabetes (n = 6,586) were randomized to a tirzepatide (dual glucose-dependent insulinotropic polypeptide \[GIP\]/GLP-1RA) treatment group. In contrast, 6,579 patients were randomized to a dulaglutide (a selective GLP-1RA) group and followed for 4 years.

The study’s primary end point was time to first major cardiovascular adverse event (MACE), a composite of death from cardiovascular causes, myocardial infarction (MI), or stroke. Secondary outcomes included cardiovascular and all-cause death; additional composite cardiovascular outcomes (including coronary revascularization and heart-failure events), kidney function change over 36 months; and changes in A1c, weight, blood pressure, and triglycerides (TG)/low-density lipoprotein cholesterol (LDL). Following the conclusion of the study, tirzepatide proved to be as safe and effective as dulaglutide for major cardiovascular events (death, MI, or stroke) in high-risk patients with type 2 diabetes, with more gastrointestinal (GI) side effects, but reported better A1c and weight loss. Interestingly, the broader composite (including revascularization) was lower with tirzepatide, as was all-cause mortality. The conclusion of this study shows that tirzepatide has good metabolic benefits and is at least comparable to dulaglutide regarding cardiovascular events, which will hopefully translate to more choice of therapies and greater access to care for patients.

Outside of weight loss and improved glycemic control benefits, researchers noted that there remains a question regarding how exactly the incretin agonist mechanism of action makes them effective against cardiovascular disease/events. The remaining question highlights a need for additional data and future research on the subject.

Comparative Cardiovascular and Safety Outcomes: Tirzepatide vs Dulaglutide

GLP-1s and Moderate Cardiovascular Risk

A second study compares the effectiveness of GLP-1 receptor antagonists on cardiovascular outcomes in patients with type 2 diabetes and moderate cardiovascular risk.This study specifically focused on the patient population whose predicted risk of experiencing a MACE, like MI or stroke, or dying from any cause was 1% to 5% in the upcoming year. The researchers cited a lack of comparative effectiveness data as stemming from the way clinicians and patients often select medications, especially GLP-1s. Oftentimes, patients and clinicians are forced to make clinical decisions based on insurance formulary preferences rather than comparative efficacy data. And those formulary decisions are largely based on manufacturer rebates and contract negotiations – not clinical effectiveness data. The surge in GLP-1 prescribing, shortages of semaglutide, and the recently available generic options for liraglutide all contributed to the development of this study, highlighting the importance of evidence-based clinical decision-making.

This study included adults with type 2 diabetes and moderate cardiovascular disease risk who initiated dulaglutide (n = 35,572), exenatide (n = 4,376), liraglutide (n = 8,843), or semaglutide (n = 33,063) between 2019 and 2021. Out of the four therapies, semaglutide and liraglutide showed the most significant benefits. Specifically, semaglutide was associated with a lower risk of MACE, expanded MACE, all-cause mortality, acute stroke, and arterial revascularization compared to dulaglutide. In addition, liraglutide was also associated with a lower risk of MACE and all-cause mortality compared to dulaglutide. The authors provide explanations regarding the differences between the four medications. One possible explanation may be tied to the mechanisms of the receptor-binding and pharmacokinetic properties. While all GLP-1s activate the same receptor mechanistically, they differ in their structure. The longer the molecular structure is able to engage with the receptor, the more sustained the signaling effects. In addition to improved glycemic control and increased weight loss, GLP-1s also exert direct cardiovascular effects, including reducing inflammatory markers, reducing inflammatory cytokines, reducing blood pressure, and potentially direct myocardial effects. However, the magnitude of such effects entirely depends on how each medication engages with the receptor.

Notably, exenatide showed noninferiority to each of the other three agents. This was a surprising discovery because exenatide had not previously demonstrated cardiovascular benefits (EXSCEL, NCT01144338). Researchers highlight the importance of real-world evidence (RWE) as a result of this significant discovery. Moreover, this underscores the importance of clinical effectiveness data as a part of the clinical decision-making process. Other surprising outcomes of this study showed no significant differences between semaglutide and liraglutide for any outcome, despite prior studies demonstrating semaglutide’s superiority. Additionally, researchers found no difference between the GLP-1s in heart failure (HF) hospitalization risk, despite semaglutide’s benefits in the STEP-HFpEF trial for HF symptoms in patients with heart failure with preserved ejection fraction (HFpEF), obesity, and type 2 diabetes. The researchers end by detailing future studies, including research on how to best care for patients with type 2 diabetes, those with obesity, and those with cardiovascular-kidney-metabolic (CKM) syndrome risk factors.

Who it affects

This issue is particularly relevant for individuals diagnosed with type 2 diabetes, obesity, or cardiovascular issues. Healthcare providers, including doctors and pharmacists, need to stay informed about these drugs’ effects to offer the best recommendations. Additionally, healthcare systems will need to adapt policies to ensure that patients can access these emerging therapies safely and effectively.

• According to the U.S. Centers for Disease Control and Prevention (CDC), about 1 in 8 Americans has diabetes, and most (90-95%) have type 2 diabetes. Research shows that while type 2 diabetes most often develops in adults 45 years and older, recently, more children, teens, and young adults are developing type 2 diabetes than in the past. Risk factors include obesity, patients who have prediabetes, and if a person has a parent, brother, or sister with type 2 diabetes, among other factors. Due to the damage that high blood sugar can cause to the body (eg, heart disease, vision loss, and kidney disease), it’s important to manage diabetes well. The CDC identified four main factors that are associated with the prevention of diabetes-related complications: mental health, physical activity, weight management, and cholesterol treatment.
• The CDC also reports that heart disease is the leading cause of death for men, women, and people of most racial and ethnic groups. Researchers highlight that the cost of health care services and medications for heart disease amounted to more than $168 billion between 2021 and 2022. While high blood pressure, high cholesterol, and smoking are key risk factors for heart disease, there are medical conditions like diabetes and obesity that increase a patient’s likelihood of developing heart disease.

GLP-1s were originally developed for managing type 2 diabetes, and through real-world evidence (RWE), they showcased clinically meaningful weight loss in patients, which granted them approval for weight management. Following their success in weight loss, GLP-1s are now being studied for their effectiveness in other conditions, including cardiovascular disease (CVD), chronic kidney disease (CKD), and obstructive sleep apnea (OSA), among other conditions.

Patient Access

As more of these agents become available, logic dictates that patient access should increase; however, both clinicians and patients alike will need to consider individual patient factors to make the best decisions possible.Equitable access to these therapies is an important topic of conversation. Issues of cost, formulary placement, utilization management, and access necessitate policy reforms to ensure equitable availability of these treatments. Additionally,issues of shortages impacting patient care have led to discussion of reserving these medications for patients with diabetes over other indications, like weight loss.

Research shows that, among income, insurance status, and semaglutide use, individuals with incomes above the median were more likely to use semaglutide than those with lower incomes. Furthermore, when comparing insurance, private insurance also significantly increased the likelihood of semaglutide use. Other factors that were significant predictors of access included education level and employment status. Researchers did observe racial and ethnic disparities, but after adjustment, the outcomes were not statistically significant. The findings highlighted significant barriers that lower-income individuals faced when it came to accessing semaglutide. The same individuals who are disproportionately affected by diabetes. This research study, like many others, emphasizes the need for policy interventions when it comes to accessibility and affordability. As medications steadily prove their clinical effectiveness and value in patients with connected conditions like diabetes, obesity, cardiovascular disease, and many more, health care providers, policymakers, manufacturers, and payors should ensure equitable access.

What changes**

• Healthcare providers should consider individual patient risks when prescribing diabetes medications, recognizing that not all treatments provide the same cardiovascular benefits.
• Policymakers need to ensure that new medications are covered by insurance to improve access for those who would benefit.
• Continued research is vital to better understand these medications’ long-term effects on heart health and other critical health outcomes.
• Regarding future research, comparing GLP-1s and SGLT2 inhibitors may provide additional information needed to make the best possible decisions for specific patients.

References

1. https://clinicaltrials.gov/study/NCT04255433
2. https://pubmed.ncbi.nlm.nih.gov/40983112/
3. https://clinicaltrials.gov/study/NCT01144338
4. https://clinicaltrials.gov/study/NCT04788511
5. https://www.cdc.gov/diabetes/about/about-type-2-diabetes.html
6. https://gis.cdc.gov/grasp/diabetes/diabetesatlas-statsreport.html
7. https://www.cdc.gov/heart-disease/data-research/facts-stats/index.html
8. https://pmc.ncbi.nlm.nih.gov/articles/PMC12303005/
9. https://pubmed.ncbi.nlm.nih.gov/38942431/
10. https://pubmed.ncbi.nlm.nih.gov/41437637/