Semaglutide 2.4 mg versus Liraglutide 3 mg for the Treatment of Obesity in Greece: A Short-Term Cost-Effectiveness Analysis

Obesity is a major global health issue with profound social and economic implications. Defined as the excessive accumulation of body fat, obesity is commonly assessed using body mass index (BMI), which is calculated by dividing a person’s weight in kilograms by the square of their height in meters (kg/m²) [1]. According to the World Health Organization, individuals with a BMI of 30 or higher are classified as obese [1]. Recent estimates indicate that 12.5% of the global population is obese, with this figure more than doubling since 1990 [1]. In Greece, the obesity rate is particularly concerning, with 27.98% of adults classified as obese and approximately 33.4% of children aged 4–12 years identified as overweight or obese [2, 3]. Recognizing the growing burden of childhood obesity, the Greek Ministry of Health has launched a national plan (2022–2026) to address this critical public health challenge [4].

Obesity is associated with significant morbidity and mortality, reduced quality of life (QoL), and decreased life expectancy. It is a well-established risk factor for numerous chronic diseases, including cardiovascular disease, endocrine disorders, musculoskeletal conditions, respiratory issues, gastrointestinal complications, and several types of cancer [5‐8]. The Global Burden of Disease study attributes 5 million premature deaths annually to obesity, with high BMI accounting for 9% of all adult disability-adjusted life years (DALYs)—a metric representing years lost owing to illness, disability, or premature death [9, 10]. Obesity reduces life expectancy by 3–8 years, depending on BMI severity, and adversely impacts health-related quality of life (HRQoL), with higher BMI linked to declines across all domains of the 36-item Short Form Survey (SF-36), a widely used HRQoL instrument assessing both physical and mental health [11‐15].

In addition to its health impact, obesity imposes a substantial economic burden. The World Obesity Atlas predicts global costs associated with overweight and obesity to rise from USD $2 trillion in 2020 to USD $4.32 trillion by 2035, representing nearly 3% of the global gross domestic product (GDP) [16]. In Greece, the economic impact of overweight and obesity was estimated at USD $4.33 billion in 2020, equivalent to 2.32% of the GDP, with more than 70% of these costs attributed to absenteeism, presenteeism, and premature mortality [16]. However, as indirect costs typically manifest over extended periods, they are excluded from this study, which adopts a short-term time horizon focusing on direct medical costs. This approach aligns with the perspective of the Greek third-party payer, the National Organization for the Provision of Health Services (EOPYY), which prioritizes pharmacy costs during negotiations with marketing authorization holders [the Ministry of Health (MoH)].

The management of obesity includes lifestyle modifications (diet and exercise) as the first-line approach, pharmacotherapy for cases where lifestyle changes are insufficient, and bariatric surgery for severe cases [17, 18]. Although lifestyle interventions are essential, they often fail to achieve long-term weight maintenance owing to physiological adaptations promoting weight regain such as reduced metabolic rate and increased appetite [19, 20]. Pharmacotherapy serves as a critical adjunct to support sustained weight loss, particularly for individuals with a BMI ≥ 30 or ≥ 27 with comorbidities, which sets the background for examining the cost-effectiveness of pharmacological options. Treatment guidelines recommend discontinuing pharmacotherapy if patients fail to achieve ≥ 5% weight loss within 3 months at maximum dosing, a criterion broadly applied across all anti-obesity drug therapies [20].

The Greek National Health System operates as a mixed healthcare system, combining elements of the Bismarck and Beveridge models, with EOPYY functioning as a monopsony that acts as the central purchaser of health services on behalf of the population [21]. In Greece, several European Medicines Agency (EMA)-approved medications for obesity, including phentermine, naltrexone-bupropion, and orlistat, are available but not reimbursed by EOPYY, requiring patients to purchase them out-of-pocket. The only reimbursed option is liraglutide 3 mg, making it a relevant comparator in this study. Semaglutide 2.4 mg, though not currently reimbursed, has shown significant efficacy in the STEP clinical trial program and represents a promising option for obesity management [22].

Resources are inherently finite in healthcare, requiring policymakers to allocate them efficiently across therapeutic categories. As the burden of obesity increases, pressure on healthcare budgets intensifies, necessitating the prioritization of treatments that are both clinically effective and cost-effective. Economic evaluation, defined as the comparative analysis of alternative courses of action in terms of both their costs and consequences, offers a robust framework for assessing new technologies [23]. The present study forms a cost-of-control analysis, a variant of cost-effectiveness analysis (CEA), which quantifies the cost of achieving specific clinically relevant targets within a short period [24, 25].

Short-term cost-effectiveness analyses assess clinical outcomes such as the proportion of patients achieving treatment targets over a 1–2-year timeframe. In this analysis, a 68-week horizon was chosen to align with available data from the STEP-8 clinical trial [22]. This approach complements traditional long-term cost-effectiveness analyses, which rely on modeling techniques to estimate the future benefits of sustained weight loss such as reductions in obesity-related complications and decreased mortality [26, 27].

Existing evidence consistently highlights the cost-effectiveness of semaglutide 2.4 mg for obesity management compared with no treatment, diet and exercise, and other anti-obesity medications, such as phentermine-topiramate, phentermine, naltrexone-bupropion, and liraglutide 3 mg in countries such as the USA, the UK, and Canada [28, 29]. However, limited research has explored the short-term cost-effectiveness of semaglutide 2.4 mg versus liraglutide 3 mg in European healthcare settings [30] where drug pricing mechanisms and reimbursement policies differ significantly. This study addresses this gap by leveraging head-to-head clinical trial data to evaluate the cost per patient achieving clinically relevant weight loss targets over 68 weeks in adults who are overweight or have obesity without diabetes, conducted from the perspective of the Greek third-party payer, EOPYY.

The findings of this study highlight the clinical and economic value of semaglutide 2.4 mg compared with liraglutide 3 mg for achieving meaningful weight loss targets in adults who are overweight or have obesity without diabetes in Greece. By demonstrating a lower CoC for semaglutide across all weight loss targets, this study provides actionable evidence to support healthcare decision-making. In the Greek healthcare context, where the economic burden of obesity continues to escalate rapidly, these findings highlight that semaglutide 2.4 mg has the potential to serve as an additional reimbursed obesity pharmacotherapy, as it demonstrates both clinical and economic merits for achieving weight loss targets. However, it should be noted that, despite its lower cost of control compared with liraglutide, semaglutide incurs higher overall treatment costs and thus cannot be considered cost-saving. Moreover, the absence of an established cost-effectiveness threshold for weight loss targets complicates the evaluation of whether its increased efficacy fully justifies the higher costs of semaglutide.

This study makes a novel contribution to literature by being the first to evaluate the short-term cost-effectiveness of semaglutide 2.4 mg versus liraglutide 3 mg using head-to-head data from the STEP-8 trial. Unlike previous studies that relied on short-term indirect comparisons or long-term modelled projections [26, 27, 30], this analysis draws on direct efficacy data, allowing for a robust assessment of the two treatments’ relative economic and clinical value. Explicitly, prior research, such as the work by Azuri et al., examined cost per 1% weight loss using data from different trials (e.g., STEP 1 and SCALE) and applied adjustments to account for heterogeneity in study populations and follow-up durations [30]. While valuable, these approaches carried inherent limitations owing to their reliance on indirect evidence and cross-trial assumptions [30]. In contrast, this study’s head-to-head trial data ensure reliability and clinical relevance, whilst the examination of additional clinically meaningful weight loss targets, including the proportion of patients achieving ≥ 5%, ≥ 10%, ≥ 15%, and ≥ 20% weight loss, offers a more comprehensive and holistic perspective compared with previous research.

The cost-of-control methodology further distinguishes this study from traditional economic evaluations, such as cost-effectiveness or cost–utility analyses, focusing on broader outcomes such as QALYs or DALYs. By linking costs directly to predefined clinical outcomes, the CoC approach offers a more targeted framework for addressing the short-term priorities of healthcare payers. This methodology aligns well with the immediate policy needs in Greece, where resources are constrained, and there is an urgent need to manage the rising clinical and economic burden of obesity.

This study highlights the importance of evidence-based reimbursement decisions grounded in robust comparative analyses for policymakers. Assessing the inclusion of semaglutide as an additional anti-obesity medication in the reimbursement list can expand patient treatment options, potentially yielding better clinical outcomes at a higher yet acceptable cost. The findings also emphasize the need for integrating similar analyses into health technology assessment processes to inform net pricing negotiations and ensure sustainable pharmaceutical expenditures across therapeutic categories.

Despite its strength, the present analysis carries limitations that must be acknowledged. The focus on short-term outcomes excludes the potential long-term benefits of sustained weight loss, such as reductions in obesity-related comorbidities, reductions in mortality, benefits in HRQoL and increases in quality-adjusted life expectancy. The analysis assumes maximum dosing per the trial protocol without accounting for real-world adherence patterns or dose modifications due to tolerability issues. However, this limitation was tackled in the deterministic sensitivity analysis, in which the different maintenance doses of semaglutide and liraglutide were altered to assess their impact on the cost of control outcomes. Also, while the STEP-8 trial reported higher discontinuation rates for liraglutide than semaglutide, costs associated with managing adverse events were not included. The reason was that, according to the STEP-8 trial, these adverse events were predominantly mild, with insignificant incremental costs from the payer’s perspective. Also, a limitation of the present analysis is that while the probabilistic sensitivity analysis (PSA) accounted for variability in clinical efficacy using standard errors directly derived from the STEP-8 trial, a similar approach could not be applied to costs owing to the unavailability of standard error data for drug acquisition costs. A PSA for costs was not conducted to ensure methodological consistency and avoid introducing potential bias or misrepresentation through arbitrary assumptions (e.g., 20%) that would directly affect the alpha and beta parameters of the gamma distribution [36].

Furthermore, focusing on semaglutide 2.4 mg and liraglutide 3 mg excludes other anti-obesity medications, such as the recently authorized tirzepatide, which could offer alternative perspectives. This decision was driven by the lack of a published network meta-analysis (NMA) examining semaglutide and other drugs and the fact that liraglutide 3 mg is currently the only reimbursed obesity pharmacotherapy in Greece. Therefore, the third-party payer would be predominantly interested in comparing a potentially reimbursed pharmaceutical product (semaglutide) with the standard of care (liraglutide) and examining whether the new medicine is cost-effective and hence meets the requirements for reimbursement. Also, only direct medical costs relevant to the third-party payer of Greece were considered (pharmaceuticals and consumables). In contrast, other direct nonmedical costs were not considered, such as staff salaries for compliance roles, training, monitoring systems, administration fees, and support services costs.

Additionally, only list prices were considered, excluding clawback, confidential discounts, or volume-based rebates that may influence drug costs. This limitation, though, was adequately tackled in the scenario analysis in which the list prices of liraglutide and semaglutide were simultaneously altered to assess whether the CoC results significantly altered. The one-way scenario analysis revealed that significant price reductions for liraglutide (> 77%) would be required to make its average CoC across all weight loss targets comparable to semaglutide. The two-way scenario analysis demonstrated that, in 8100 potential pricing scenarios, liraglutide’s cost of control remained economically disadvantageous at 94.23% of cases. This highlights the robustness of the base case results, even in the face of potential list pricing shifts.

Finally, the analysis did not account for indirect costs, such as productivity losses, premature mortality, absenteeism and presenteeism, and early retirement costs, which could further enhance the perceived value of semaglutide. Future research should prioritize conducting long-term cost-effectiveness analyses incorporating all relevant comparators and adopting a societal perspective to comprehensively capture both direct and indirect costs and the long-term benefits of sustained weight loss. Additionally, as trial-based data are subject to uncertainty surrounding baseline clinical and demographic characteristics, Greek-specific real-world data should be captured to validate the economic results of the present analysis. For example, the cost of control (CoC) of semaglutide versus liraglutide should be examined across different subgroups, such as patients who are overweight or have obesity with complications and diabetes, as STEP-8 focused on individuals without diabetes. Since both medications are also authorized for treating diabetes and obesity, it would be valuable to explore the CoC for additional dual or triple endpoints that encapsulate both obesity and diabetes outcomes. This would provide a more comprehensive understanding of their clinical and economic potential across varied patient populations. Such an analysis would address a significant gap, as individuals with diabetes often have distinct clinical and economic considerations that may influence treatment efficacy, adherence, and cost-effectiveness.

From a policy perspective, the present study’s findings provide crucial insights into the value of semaglutide as an additional obesity pharmacotherapy in Greece. Semaglutide’s lower cost of control than liraglutide offers an economic argument for its potential inclusion in the list of reimbursed medicinal products. However, given that obesity is a chronic, complex, and multifactorial disease, pharmacotherapy should be viewed as one component of the broader framework of multi-disciplinary actions, including lifestyle modifications, behavioral counseling, nutritional support, physical activity interventions, and, when necessary, surgical treatments. Policymakers must weigh the clinical benefits and cost implications of reimbursing semaglutide versus other available therapies, ensuring that any decisions are adequately justified, especially within constrained healthcare budgets. Given the scarcity of health resources, prioritizing the most cost-effective treatments is crucial, as every euro allocated to a specific drug carries an opportunity cost, limiting investment in other critical healthcare interventions.

Given the high prevalence of obesity and the correspondingly sizeable eligible population for anti-obesity pharmacotherapy, coupled with the high drug acquisition costs of new anti-obesity medications, policymakers face a critical challenge in ensuring the sustainability of healthcare budgets. To address this, decision-makers should consider implementing outcome-based agreements that align payment with the clinical effectiveness of treatments [37]. Such agreements enable healthcare systems to pay for the most efficacious therapies while ensuring that truly innovative medications are rewarded for their added value [37]. By linking reimbursement to real-world outcomes, outcome-based agreements can foster a more efficient allocation of resources, mitigate financial risks associated with large eligible populations, and incentivize the rewarding of genuinely innovative treatments.

Finally, a multi-stakeholder approach is essential for effectively addressing the growing obesity epidemic, necessitating collaboration between policymakers, third-party payers, medical associations, patient advocacy groups, pharmaceutical companies, public health experts, health economists, and academic institutions. Strengthening the national obesity task force could provide a structured platform for stakeholders to share insights, align objectives, and develop comprehensive, evidence-based strategies and policies. Such initiatives would ensure that diverse perspectives are considered, fostering innovative solutions and coordinated efforts to tackle obesity holistically.

This study found that semaglutide 2.4 mg demonstrated a lower cost of control than liraglutide 3 mg across all examined weight loss targets in adults who are overweight or have obesity without diabetes in Greece. While no established willingness-to-pay threshold exists for weight loss outcomes at 68 weeks, semaglutide’s lower cost of control and higher efficacy versus liraglutide suggest it is likely to be a cost-effective treatment option.