GLP-1 receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists—collectively termed nutrient-stimulated hormone therapies—are now endorsed in expert consensus clinical guidance for their dual therapeutic effects: clinically meaningful weight loss and reduction of cardiovascular risk in adults with obesity. These therapies fill a critical gap between lifestyle intervention and bariatric surgery, offering a pharmacologic alternative with demonstrated cardiometabolic benefits.
More than 40% of U.S. adults have obesity (body mass index [BMI] ≥30 kg/m²), and nearly 10% meet criteria for severe obesity (BMI ≥40 kg/m²). Obesity significantly increases the risk of cardiovascular disease (CVD), including heart failure (particularly with preserved ejection fraction [HFpEF]), coronary artery disease, atrial fibrillation, sudden cardiac death, and stroke. Weight loss of 10% to 15% is associated with CVD risk reduction, while losses >15% are linked to lower cardiovascular mortality and improved outcomes in HFpEF.
Lifestyle interventions typically achieve approximately 5% weight loss and are not consistently associated with reductions in major cardiovascular events. Bariatric surgery may result in approximately 25% weight loss and reduced mortality but is not feasible or acceptable for all patients. Nutrient-stimulated hormone (NuSH) therapies offer a medical alternative with improved tolerability and sustained benefit.
NuSH agents include liraglutide (GLP-1 receptor agonist), semaglutide (GLP-1 receptor agonist), and tirzepatide (dual GLP-1/GIP receptor agonist). These medications promote weight loss by modulating appetite, satiety, insulin secretion, and gastric emptying through hormonal signaling pathways. Clinical trials have demonstrated mean weight reductions of 8.0% with liraglutide, 14.9% with semaglutide, and 20.9% with tirzepatide at maximum doses.
Cardiovascular outcome trials have also shown benefit. In the SELECT trial, semaglutide reduced the composite of cardiovascular death, myocardial infarction, and stroke by 20% in adults with overweight or obesity and established atherosclerotic CVD. In the SUMMIT trial, tirzepatide reduced both cardiovascular death and hospitalizations in adults with HFpEF and obesity (HR for composite: 0.62; 95% CI, 0.41–0.95).
Eligibility for NuSH therapies is based on BMI: ≥30 kg/m², or ≥27 kg/m² in the presence of weight-related comorbidities such as type 2 diabetes, hypertension, or obstructive sleep apnea. These therapies are initiated with low-dose titration to minimize gastrointestinal adverse effects, which may include nausea, diarrhea, and constipation. Approximately 4% to 7% of patients discontinue therapy due to side effects. Contraindications include personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.
NuSH therapies are intended for long-term use. Discontinuation frequently results in weight regain, reinforcing the need for sustained therapy. Guidance supports a multidisciplinary approach that includes physicians, dietitians, behavioral specialists, and pharmacists to help patients manage obesity and related conditions.
Access remains a key barrier. In the United States, annual costs may exceed $14,000 per patient for semaglutide and $15,700 for liraglutide. Reimbursement is often limited to individuals with additional qualifying conditions such as type 2 diabetes. As a result, patients may seek unregulated access to compounded alternatives, which pose safety concerns.
NuSH therapies represent a cornerstone in the evolving paradigm of medical obesity treatment. Beyond weight loss, they offer meaningful reductions in cardiovascular risk, particularly among patients with established CVD or HFpEF. As the authors concluded, “Obesity management by the cardiovascular community needs to be embraced, given both the prevalence of obesity and the impact it has on many forms of CVD.”
Author disclosures of relationships with relevant entities are listed in the original publication.
Source: JACC
