Semaglutide's New Indication Highlights Growing Role of GLP-1 Receptor Agonists

Since their first identification as therapeutic agents in 2005, glucagon-like peptide-1 receptor agonists (GLP-1s) have evolved into essential agents in treating diabetes and its comorbidities.¹ These agents were first approved for lowering blood sugars in patients with diabetes.¹ Clinical trials over the past twenty years have also established their effects on weight loss and cardiovascular outcomes in that patient population.² A recent FDA approval for semaglutide (Wegovy; Novo Nordisk) has expanded the indications to improve cardiovascular outcomes in patients with obesity who do not have diabetes, which is a significant step forward.³

Results from a recent study named the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial (NCT03574597) indicated a significant decrease in adverse cardiovascular events (ACEs) in overweight patients without diabetes given semaglutide (Ozempic and Rybelsus; Novo Nordisk).⁴ Clinical trials have established the cardiovascular benefits of GLP-1 receptor agonists in patients with diabetes with active cardiovascular disease. However, this was the first study to demonstrate improved outcomes in patients without diabetes.

GLP-1 Mechanism of Action

The approved GLP-1 receptor agonist agents in the United States include semaglutide, liraglutide (Victoza; Novo Nordisk), dulaglutide (Trulicity; Eli Lilly), and exenatide (Byetta; Amylin and Bydureon; AstraZeneca). Semaglutide is available in long-acting injectable (Wegovy and Ozempic) and daily oral tablet (Rybelsus) formulations, while exenatide has short-acting (Byetta) and long-acting (Bydureon) injectable forms. Liraglutide is a short-acting injectable, while dulaglutide is a long-acting injectable medication.

Secreted by enteroendocrine cells in the presence of food in the intestine, GLP-1 is a hormone that causes a cascade of effects that lower blood glucose. In diabetes, its levels are believed to be reduced or absent. The GLP-1 receptor agonists take the place of the endogenous hormones and stimulate pancreatic islet cells, resulting in increased glucose-dependent insulin release. They have also been shown to slow gastric emptying, reduce post-meal glucagon release, and increase satiety.

The known benefits of GLP-1 inhibitors in diabetic patients include reductions in HbA1c, weight, lipid status, and blood pressure. The decrease in HbA1c ranges from 0.8% to 1.5%5, and the average weight loss is 2.9 kilograms.⁶ Several agents also reduce major ACEs, such as heart attack, stroke, and cardiovascular death.

Side effects of GLP-1 receptor antagonists are generally mild and short-term, consisting primarily of gastrointestinal symptoms of nausea, vomiting, and diarrhea. These symptoms typically occur at therapy initiation or during dosing increases, but they gradually disappear and are easily managed. Current recommendations are to start patients on low doses before titrating up. Patients are advised to eat frequent small meals and avoid fried or fatty foods. Notably, hypoglycemia is rarely reported with these agents.

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GLP-1 Place in Therapy

According to the American Diabetes Association’s 2024 Standards of Care in Diabetes, the class of GLP-1 receptor inhibitors is among the first choices as an adjunct therapy to metformin in treating elevated HbA1c if the marker remains high after a 3-month trial of metformin alone.⁷ Standards of care also recommend these agents for initial therapy if patients cannot tolerate metformin.⁷

Specific GLP-1 receptor agonists join sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) as preferred add-on agents in the presence of active cardiovascular disease. According to the standards of care, semaglutide, liraglutide, and dulaglutide are recommended.⁷ The cardioprotective effects of GLP-1 receptor agonists and SGLT-2 inhibitors may be additive, and in select high-risk patients, agents from both classes may be used together.⁷

Review of GLP-1 CV Benefits

Patients with diabetes have a 2- to 4-fold increased risk of cardiovascular disease compared to those who do not have the disease.⁸ It is estimated that half the deaths in adult patients with diabetes are the result of cardiovascular events.⁹ When studied individually, 3 GLP-1 receptor antagonists effectively reduce ACEs. Notably, 3 long-acting available agents – liraglutide, semaglutide injectable (not oral), and dulaglutide – were effective and are now approved by the FDA for use in patients with diabetes and cardiovascular disease. Neither oral semaglutide nor exenatide showed evidence of benefit.

According to a meta-analysis of cardiovascular outcome trials, the long-acting GLP-1 receptor agonists demonstrated an overall relative risk reduction for major ACE outcomes of 14%.¹⁰ The effect size was 16% for stroke prevention, 12% for cardiovascular death, and 9% for heart attack prevention.¹¹

Proposed mechanisms for improving cardiovascular outcomes include the agent's effects on weight loss, lipid-lowering, hypertension, and anti-inflammatory effects. Among the proposed anti-inflammatory actions are improving endothelial and left ventricular function, promoting plaque stability, and decreasing platelet aggregation.

New Role for Semaglutide

Semaglutide's FDA approval for non-diabetic patients with cardiovascular disease came after the completion of the SELECT trial. A study group of 17,604 patients with a body mass index of 27 or greater were enrolled in the multi-center, double-blind design. Investigators randomized patients to receive semaglutide 2.4 mg weekly or placebo. Exclusion criteria included a previous diagnosis of diabetes or an HbA1c of 6.5% or higher. Investigators followed patients for a mean duration of 34.2 months, with the primary end point being a composite end point of death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke. Semaglutide treatment reduced the risk by 20% in the active study population. Adverse effects included gastrointestinal complaints, which led to discontinuation in a larger percentage of the semaglutide group. Gallbladder-related disorders were also higher in the semaglutide group than in the placebo, a previously known association with the agent.⁴

Future Considerations

While this study establishes the cardiovascular benefits of semaglutide in non-diabetic patients, liraglutide and dulaglutide have yet to be studied in these patient populations. Future studies may be warranted to determine if those 2 agents maintain their cardiovascular benefits in a patient population with obesity and without diabetes.

Conclusion

The approval of semaglutide to treat patients who are overweight or obese with cardiovascular disease in the absence of diabetes is a significant step in the continuing evolution of the clinical utility of GLP-1 receptor agonists. The agent, and perhaps others in its class, will be valuable tools for clinicians looking to treat multiple indications, including diabetes, obesity, and cardiovascular disease.

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