How would the use of Semaglutide impact the Chilean population? An estimated analysis following the <scp>SELECT</scp> trial approach

Obesity has reached epidemic levels, affecting both high- and low-middle-income countries.1-3 According to the latest Global Burden of Disease (GBD) Study, more than 2.1 billion people worldwide were living with overweight or obesity in 2021.2 In Chile, the Chilean National Health Survey (CNHS) 2016–2017 highlighted that 74.2% of the population was either overweight or obese,4 while, more recently, the World Obesity Federation stressed that Chile has the highest prevalence of obesity in South America (42% of the total population). Obesity is also one of the main precursors of diabetes and cardiovascular diseases.5 For some years, Semaglutide—a glucagon-like peptide-1 (GLP-1) receptor agonist—has been shown to effectively lower the risk of adverse cardiovascular events in individuals with type 2 diabetes.6 However, recent results from the Semaglutide Effect on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial6 demonstrated that Semaglutide 2.4 mg weekly reduced the risk of major adverse cardiovascular events (MACE) in obese adults without diabetes, which has immensely expanded its scope of use. Yet, despite the documented benefits of this medication, its potential impact at the population level in Chile remains uncertain. While prior work has reported the potential population-level benefit of wider Semaglutide use in the United States,7 no such data is available from Chile. Therefore, considering the potential cost-effectiveness benefits, we aimed to address the following questions: What percentage of the adult Chilean population is Semaglutide eligible as per the SELECT criteria? And, how many MACE and all-cause deaths would be avoided if this drug could be widely used in the Chilean population? This prospective research letter utilised data from the CNHS 2016–2017. The CNHS was a survey conducted using a probabilistic, stratified, and multistage sample of 6233 individuals aged 15 years or older, ensuring national and geographical representativeness. Additional details regarding the Chilean cohort survey can be found elsewhere.4 We first estimated the number of adults who met the SELECT trial inclusion criteria by applying CNHS sample weights (SELECT trial criteria: adults >45 years with a body mass index (BMI) >27 kg/m2, and with a pre-existing diagnosis of atherosclerotic cardiovascular disease defined as coronary artery disease, stroke, peripheral arterial disease, or prior myocardial infarction). Moreover, as the aim of this modelling study was to determine the proportion of the Chilean population eligible for Semaglutide based on the SELECT criteria, participants with type 2 diabetes were excluded from eligibility for Semaglutide. Then, for the whole cohort, we also calculated their 10-year MACE risk applying the Predicting Risk of Cardiovascular Events (PREVENT) calculator, a recently developed risk model recommended by the American Heart Association to guide preventative therapies.8 With this baseline predicted risk, we applied the treatment benefit (with regard to weight reduction and lowering of systolic blood pressure over the study period) that was reported by the SELECT trial to calculate the projected new readings with Semaglutide therapy. To model the stochastic variation in treatment benefit across patients, we used a triangular distribution for each effect. These values were then utilised to obtain the individual revised projected 10-year MACE risk as per the PREVENT criteria. Utilising the baseline and revised PREVENT 10-year MACE risk for the whole cohort, we applied the weights provided to summarise this effect for the entire Chilean population and calculated the relative risk reduction (RRR), absolute risk reduction (ARR), events prevented, and the number needed to treat (NNT). 100 000 bootstraps were used to obtain the 95% confidence intervals (95% CI) in each case. For this analysis, we assumed that all eligible people received Semaglutide for the mean duration of the SELECT trial (34.2 months).6 We used R 4.3.2 for all statistical analyses and the ‘survey’ package for weighted modelling. Readers can request R scripts used for the analysis from the corresponding author; data can be freely downloaded here https://epi.minsal.cl/resultados-encuestas/. A summary of methods is available in Figure 1. On weighted analysis, 14 518 969 Chilean residents (mean age 43.2 (SE 0.4) years, female 50.9%) were studied. The observed mean systolic blood pressure (mmHg) was 123.8 (SE 0.4), and BMI was 28.5 kg/m2 (SE 0.1). The prevalence of type 2 diabetes, stroke, peripheral arterial disease, and coronary artery disease was 11.1%, 2.6%, 4.8%, and 9.7%, respectively. Only 42% have never smoked, with the remaining either active or past smokers. From the entire Chilean population, 493 949 (3.4% of the total population) fitted the SELECT criteria and were potentially eligible for Semaglutide therapy. The weighted average baseline 10-year risk for MACE, according to the PREVENT score, in those eligible for Semaglutide therapy [7.8% (SE 0.5)] was higher than that ineligible for Semaglutide therapy [7.1% (SE 0.5)]. Modelling that all eligible people received Semaglutide therapy, the observed population-level effect would be a 10-year RRR and ARR of 3.56% (95% CI: 3.36; 3.76), and 0.28% (95% CI: 0.26; 0.29), respectively. Additionally, among the 493 949 people who received Semaglutide therapy over a 10-year time span, 1235 (95% CI: 1164; 1307) MACE events would potentially be prevented; therefore, 356 (337, 378) patients are needed to treat (NNT) to avoid one MACE event. Using data from the CNHS 2016–2017, we identified that 3.4% of the population may meet the SELECT trial criteria for Semaglutide therapy. If all were treated, more than 1000 MACEs could be prevented over a decade. Semaglutide has been shown to produce significant weight loss over a 4-year period in individuals in the United States.9 Even knowing the benefits of Semaglutide and the promising results this research letter identified, access to the medication in Chile is severely limited due to the absence of financial protection or insurance coverage. Patients must, therefore, pay out of pocket at an approximate cost of 230 USD per month (CLP 220915). To contextualise, this amount represents half of the reported average income of people included in the analyses (CLP 476318) and nearly half of the average monthly per capita disposable household income in the country (CLP 555437).10 In a setting where out-of-pocket spending accounts for 39% of total health expenditure,11 such costs make the medication largely inaccessible for much of the population who could benefit from it. Moreover, Semaglutide may also lead to side effects that should be carefully considered when evaluating its overall cost-effectiveness and accessibility.12 In Chile, Semaglutide (commercialised as Ozempic)13 is formally indicated for type 2 diabetes, but even for this approved use, it does not have insurance coverage. In addition, periodic shortages have been reported, partly related to unsupervised use for rapid weight loss, likely influenced by social media promotion and informal commercialisation.14 Even if previous research in Chile has shown positive results in type 1 diabetes adults using lower concentrations of Semaglutide (0.5 mg weekly instead of 2.4 mg),15 further studies are still required in the country to investigate whether our estimated results align with the reality in Chile. Even though this is the first study to address these research questions in a nationally representative sample of the Chilean population, data were collected several years ago; therefore, a higher proportion of the Chilean population may fulfil the SELECT criteria today. Moreover, the MACE outcome reference was estimated using the original SELECT trial placebo arm, which corresponds to the American population and may differ significantly from the Chilean reality. On the other hand, we also excluded people younger than 45 years, as the original SELECT trial did, but younger participants may also benefit from the treatment. Finally, as per any observational study, causality cannot be inferred. In conclusion, if broadly available, around 3.5% of the Chilean population would be eligible for the SELECT trial treatment and would positively impact premature CVD and all-cause mortality in the country. We thank all participants for their co-operation and the Chilean Health Ministry and Department of Public Health, The Pontificia Universidad Católica de Chile for commissioning, designing and conducting the CNHS 2016-2017. None. The authors declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70260. Data can be downloaded at: https://epi.minsal.cl/resultados-encuestas/.