The Intersection of Clinical Efficacy and Economic Sustainability
The landscape of cardiovascular medicine is undergoing a seismic shift with the introduction of glucagon-like peptide-1 (GLP-1) receptor agonists. While initially approved for the management of type 2 diabetes, medications like semaglutide have demonstrated profound benefits in reducing major adverse cardiovascular events (MACE) in patients with overweight or obesity. However, as clinical adoption expands, the question of economic viability looms large. A recent study published in JAMA Cardiology by Hennessy et al. (2026) provides a critical analysis of the cost-effectiveness and budget impact of semaglutide for the secondary prevention of cardiovascular disease (CVD) among US adults without diabetes.
Highlights of the Simulation Study
– Semaglutide treatment is projected to avert approximately 358,400 major adverse cardiovascular events (MACE) over the lifetime of the currently eligible US population.
– At the 2023 net price of $8,604 annually, the incremental cost-effectiveness ratio (ICER) is $148,100 per quality-adjusted life-year (QALY) gained.
– To achieve a standard cost-effectiveness threshold of $120,000 per QALY, an 18% reduction in the annual drug cost (to approximately $7,055) is required.
– The total annual health care spending in the US is projected to increase by $23 billion if semaglutide is fully integrated into the secondary prevention pathway for this specific cohort.
Background: The Residual Risk in Secondary Prevention
Despite the success of statins, antiplatelet therapy, and antihypertensive agents, patients with a history of myocardial infarction or stroke remain at high risk for recurrent events. The SELECT trial recently demonstrated that semaglutide (2.4 mg) reduced the risk of MACE by 20% in adults with established cardiovascular disease and obesity but without diabetes. While the clinical benefit is clear, the high cost of GLP-1 therapies creates a significant barrier to widespread implementation and raises concerns regarding the long-term sustainability of the US healthcare budget.
Study Design: The CVD Policy Model Framework
The researchers utilized the CVD Policy Model, a well-validated state-transition simulation model of cardiovascular outcomes and costs in the US population. This study focused on a specific cohort: US adults aged 45 years or older with a BMI of 27 kg/m² or higher and a documented history of myocardial infarction or stroke, specifically excluding those with diabetes.
The simulation incorporated a lifetime horizon, adopting a health-system perspective. The primary intervention was the addition of weekly subcutaneous semaglutide to usual care. The model accounted for various factors, including the 2023 net price of semaglutide ($8,604 per year), the costs of treating cardiovascular events, and the quality-of-life improvements associated with weight loss and event prevention.
Key Findings: Health Benefits vs. Economic Costs
Projected Health Benefits
The model estimates that approximately 4 million US adults currently meet the criteria for semaglutide therapy for secondary CVD prevention. Implementing treatment in this cohort would result in a substantial reduction in the national burden of disease. Over the lifetime of these individuals, the therapy is projected to avert 358,400 MACE, including cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes. This translates to significant gains in quality-adjusted life-years (QALYs) across the population.
Cost-Effectiveness and the ICER
The incremental cost-effectiveness ratio (ICER) is a standard metric used to determine if a medical intervention provides sufficient value for its cost. The study found that at the current net price of $8,604, the ICER for semaglutide is $148,100 per QALY. In the context of the US healthcare system, interventions are often considered high-value if they fall below $50,000 per QALY and intermediate-value if they are between $50,000 and $150,000 per QALY. While semaglutide falls within the intermediate range, it exceeds the $120,000 threshold often used by health economists and policy makers to justify broad coverage.
The Budget Impact Challenge
Perhaps the most striking finding is the projected impact on national healthcare spending. The study estimates that treating the eligible population would increase annual US health care expenditures by $23 billion. This figure represents a significant challenge for both Medicare and private insurers, particularly as the demand for GLP-1 therapies continues to surge for other indications, such as obesity management and primary prevention.
Sensitivity Analysis: Finding the Economic Sweet Spot
The researchers performed sensitivity analyses to identify the conditions under which semaglutide would become more cost-effective.
The 18% Price Threshold
If the annual cost of semaglutide were lowered by 18%—from $8,604 to $7,055—the ICER would drop to $120,000 per QALY. This price point represents a potential target for Medicare price negotiations under the Inflation Reduction Act. Furthermore, at the cash price currently available to some self-paying customers (approximately $5,988 per year), semaglutide is already highly cost-effective, with an ICER of $99,600 per QALY.
Impact of Patient Age and Baseline Risk
The cost-effectiveness also varied based on patient characteristics. The therapy tended to be more cost-effective in patients with a higher baseline risk of recurrent cardiovascular events and those at the younger end of the eligible age spectrum, as they have more life-years to benefit from the prevention of MACE.
Expert Commentary and Clinical Interpretation
From a clinical perspective, semaglutide represents one of the most significant advancements in secondary prevention in the last decade. However, physician-scientists must balance the enthusiasm for these results with the reality of healthcare access.
One limitation of the study is that it relies on data from the SELECT trial, which may not fully represent the diversity of the real-world US population. Additionally, the model assumes lifetime adherence to therapy, which may be difficult to achieve given the potential for gastrointestinal side effects and the high out-of-pocket costs for many patients.
Furthermore, the study highlights a critical policy gap. While semaglutide is cost-effective at lower price points, the current tiered pricing and rebate structures in the US mean that the actual price paid varies wildly between payers. This lack of transparency complicates efforts to establish a uniform standard of care based on value.
Conclusion: Navigating the Future of GLP-1 Therapies
The study by Hennessy et al. underscores that semaglutide is a clinically potent tool for secondary cardiovascular prevention that offers meaningful health benefits to millions of Americans. However, its current price point places it on the edge of what is traditionally considered cost-effective in the United States.
For semaglutide to become a cornerstone of secondary prevention, stakeholders—including pharmaceutical manufacturers, government regulators, and insurers—must find common ground on pricing. A reduction in cost by approximately 18% would align the drug’s price with its clinical value, potentially expanding access while managing the substantial $23 billion annual budget impact. As Medicare price negotiations continue, these findings provide a data-driven roadmap for ensuring that life-saving therapies remain both accessible to patients and sustainable for the healthcare system.
References
1. Hennessy S, Penko J, Bellows BK, et al. Cost-Effectiveness of Semaglutide for Secondary Prevention of Cardiovascular Disease in US Adults. JAMA Cardiol. 2026;11(3):229-238. doi:10.1001/jamacardio.2025.41637062.
2. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Steering Committee and Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Overweight or Obesity who do not have Diabetes. N Engl J Med. 2023;389(24):2221-2232.
3. Neumann PJ, Cohen JT. Cost-Effectiveness of GLP-1 Receptor Agonists: A Review of the Evidence and Policy Implications. Health Aff (Millwood). 2024;43(2):180-188.