Background
Obesity presents a significant clinical and public health concern, with prevention and management emerging as global priorities [
1]. It is characterized by abnormal or excessive fat accumulation, which can impair health and increase the risk of long-term complications [
2]. In Portugal, nationwide surveys have revealed a prevalence of obesity ranging from 22 to 29%, while the prevalence of overweight ranges between 35% and 39% [
3,
4]. Overweight and obesity pose a significant risk for various chronic diseases, including among others type 2 diabetes (T2D), cardiovascular diseases, asthma, osteoarthritis and different cancers with great impact on health and wellbeing [
2,
5].
The impact of obesity extends beyond health, with substantial economic consequences affecting individuals, caregivers, the healthcare system, and society as a whole. In Portugal, people with obesity and overweight contribute to a direct annual cost of 1.2 billion euros, equivalent to 0.6% of the country’s wealth. The diseases most responsible for these healthcare costs include type 2 diabetes, stroke, ischemic heart disease, and chronic kidney disease. Notably, the cost of treating these diseases is 88 times higher than the cost of managing obesity itself, exceeding 13 million euros annually [
6].
Preventing and managing obesity and overweight pose significant challenges due to their complex and multifactorial nature, involving genetic, physiological, behavioral, and environmental factors [
7], with international guidelines recommending various therapies, including lifestyle and behavioral interventions, pharmacotherapy, and bariatric surgery [
8‐
10]. Despite the potential for significant health improvements, lifestyle interventions such as diet and exercise (D&E) often result in modest weight loss over short periods of time, with many patients facing challenges with metabolic adaptation and difficulties in maintaining D&E practices, which can contribute to weight regain [
11].
Recommendations from the Portuguese Society for Obesity Research (Sociedade Portuguesa para o Estudo da Obesidade, SPEO) state that pharmacological treatment for obesity should be considered for people with Body mass index (BMI) ≥ 30 kg/m2 or BMI between 27 kg/m2 and 29.9 kg/m2 and at least one comorbidity who have not achieved at least 5% weight loss between 3 and 6 months through lifestyle interventions [
12]. For patients with severe obesity and associated comorbidities, the Directorate-General of Health (Direção Geral da Saúde, DGS) recommends referral to an Obesity Treatment Centre, with bariatric surgery as an option for patients for whom nonsurgical weight reduction measures have failure for at least one year [
13]. Reimbursement for effective pharmacotherapy for obesity is limited in Portugal.
Semaglutide (Wegovy®) 2.4 mg injection is a long-acting glucagon-like peptide-1 (GLP-1) analogue, approved by the European Medicines Agency (EMA), that promotes weight loss via slowing down gastric emptying and thereby reducing hunger and increasing satiety [
14]. Approximately 5,000 patients enrolled in five phase 3 trials– the Semaglutide Treatment Effect in People with obesity (STEP) program. In STEP 1 trial, patients who received semaglutide 2.4 mg had clinically significant weight loss (at least a 5% reduction in weight from baseline level) compared with placebo (weight reduction: 14.9% vs. 2.4% at week 68;
P < 0.001) [
14], and superior weight loss at 68 weeks when compared with placebo in STEP 2 trial for weight management in patients with overweight or obesity and T2D [
15].
This study aimed to assess the cost-effectiveness of semaglutide 2.4 mg in combination with D&E compared to D&E alone for the treatment of adults with obesity (BMI ≥ 30 kg/m2) with one or more weight-related comorbidities, from the perspective of the Portuguese National Health Service (NHS).
Discussion
Semaglutide 2.4 mg was estimated to be cost-effective compared with D&E alone, in adults with obesity (BMI ≥ 30 kg/m2) and at least one obesity-related complication from the perspective of the Portuguese NHS.
Efficacy and safety data from STEP 1 and STEP 5 trials used in the cost effectiveness analyses provide robust evidence regarding the effectiveness of semaglutide 2.4 mg in reducing weight, managing blood pressure, controlling lipid levels, and improving glycemic control when compared to relying solely on diet and exercise. The utility data used in these analyses, which inform baseline values and consider age, gender, and BMI, were derived from reported data from STEP 1, and converted to utility weights using country-specific preferences. As a result, the QALY outcomes obtained can be generalized to the broader Portuguese population.
Other studies have estimated the cost effectiveness of semaglutide 2.4 mg in the United Kingdom, Canada, and the United States. Sandhu et al. [
37] estimated semaglutide 2.4 mg to be cost-effective against D&E alone with an ICER of £14,827/QALY gained over a lifetime horizon, from the perspective of the NHS and Personal Social Services. Olivieri et al. [
38] assessed the cost-effectiveness of weight-management pharmacotherapies approved by Canada Health, from a societal perspective, and have concluded semaglutide 2.4 mg to be the most cost-effective treatment– considering a WTP threshold of CAD 50,000 per QALY– when compared with D&E or orlistat alone, and to dominate other pharmacotherapies, such as NB-32 or liraglutide 3.0 mg. Kim et al. [
39] estimated semaglutide 2.4 mg to be cost-effective against other anti-obesity medication (liraglutide 3 mg, phentermine-topiramate, and naltrexone-bupropion), D&E and no treatment, over a lifetime horizon, from a societal perspective, with ICERs varying between $27,113 (vs. no treatment) to $144,296 (vs. phentermine-topiramate), and the ICER for D&E being $22,138.
Although results exhibited variability due to changes in a few parameters and assumptions, results remained robust in all sensitivity and scenario analyses. Additionally, scenario analyses indicate that semaglutide 2.4 mg can be considered cost-effective when responders are assumed to continue treatment for up to six years. Nevertheless, the assumptions made about the continuous use of D&E in non-responders, along with the efficacy estimate applied with a stopping rule in the base case analysis, may have on the one hand resulted in an underestimation of the potential benefits of semaglutide 2.4 mg, however, this may be more representative of its real-world utilization in the Portuguese setting. Additionally, although comprehensive but not exhaustive, the inclusion of complications related to obesity in the model was limited to those with the highest disease and economic burden, whereby the benefits and potential cost savings of weight loss and related complications may go well beyond those considered. The analysis on different subpopulations showed semaglutide 2.4 mg to be cost effective in patients with BMI ≥ 30 kg/m2 but not in patients in BMI ≥ 35 kg/m2. In both analyses, the incremental benefits of semaglutide 2.4 mg against D&E in avoiding cardiovascular events were marginal, which may be explained by these being lower risk populations. Additionally, the average age of these populations were lower than the average age in the base case analysis (46 vs. 48 years in the population with BMI ≥ 30 kg/m2; and 45 vs. 48 years in the population wjth BMI ≥ 35 kg/m2), considering that endometrial and breast cancers were applied in the model post menopause only (with a menopausal average age of 48 years), the benefits accrued with a 2-year weight-loss in this population were smaller compared to a cohort receiving treatment at and post-menopause.
This study has some limitations pertaining to the model structure and parameters. First, there is uncertainty regarding whether a short-term reduction in weight and improvement in other cardiovascular risk factors, depending on the duration of treatment, will lead to a decrease in the occurrence of complications and mortality in individuals who have been obese for an extended period of time. The Swedish Obese Subjects trial [
22] provides evidence that supports this. However, it is worth noting that the average weight loss achieved through bariatric surgery in this trial was approximately 23% in the first year, and was maintained at 18% up to 20 years after the initial surgery [
40]. While other case-control studies [
41] have explored the association between weight reduction and obesity-related complications, longer-term studies and other methodologies are needed to establish a causal link between the weight loss achieved with semaglutide and the reduction or delay of complications over an individual’s lifetime. Such evidence does exist for semaglutide in individuals with T2D, CV disease, or chronic kidney disease (SUSTAIN-6 NCT01720446) [
42]. In this context, lower doses of semaglutide (0.5 and 1.0 mg) were significantly associated with a 39% reduction in non-fatal stroke compared to placebo over a median follow-up of 2.1 years, and a non-significant 26% reduction in non-fatal myocardial infarction compared to placebo.
Other limitations pertain to the selection of risk equations. One primary concern is that none of the risk equations employed in the analysis were estimated for the Portuguese population. Therefore, there is uncertainty regarding the extent to which the overall level of risk utilized in the model, as well as the reduction in risks, can be generalized to the Portuguese population. There are, at present, no available risk equations for the Portuguese population. Therefore, the QRisk3, QDiabetes, and UKPDS82 risk equations based on the UK population, may be suitable proxies.
Moreover, efficacy data for semaglutide beyond the duration of the STEP 1 (68 weeks) and STEP 5 (104 weeks) trials are lacking. Real-life estimates are needed to determine the extent of treatment continuation and assess its long-term efficacy. It is only through the availability and use of the product in clinical practice that real-world data on its long-term costs and benefits can be obtained.
Additionally, obesity is associated with several complications, many of which not included in the model. The model has however included those complications that were considered most impactful in terms of disease and economic burden. With this in mind, the full spectrum of potential benefits and cost savings related to weight reduction could not be captured, and current results may be an underestimation of the full impact of this treatment option. For instance, the model did not account for the microvascular complications arising from the progression of T2D and the decline of beta-cell function leading to insulin resistance, hence nor the related changes in costs and quality of life over time. Instead, a single cost and quality of life parameter for T2D were applied throughout the analysis period. This approach may have resulted in an overestimation of T2D costs in the early years and an underestimation in the later years, potentially offsetting each other’s effects.
Finally, there may be some double-counting of mortality cases in the model when both disease-specific mortality and all-cause BMI-dependent mortality are considered. Yet, the inclusion of mortality due to diseases modelled only can be expected to result in an underestimation of mortality [
17,
18], and more so in those with higher baseline BMI [
43]. Indeed, many population-level studies, including Bhaskaran et al. [
35], have found an increased risk of death with increasing weight going beyond the causes currently considered in the COM, such as communicable diseases, liver cirrhosis and liver and kidney cancers, heart failure and atrial fibrillation to name a few. Henceforth, without considering the mortality due to these additional causes, the total life expectancy predicted with the model may lose face validity, especially in populations with higher BMI.
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