The cost‐effectiveness of pharmacotherapy and lifestyle intervention in the treatment of obesity

Summary Background The Food and Drug Administration has approved several pharmacotherapies for the treatment of obesity. This study assesses the cost‐effectiveness of six pharmacotherapies and lifestyle intervention for people with mild obesity (body mass indices [BMIs] 30 to 35). Methods A microsimulation model was constructed to compare seven weight loss strategies plus no treatment: intensive lifestyle intervention, orlistat, phentermine, phentermine/topiramate, lorcaserin, liraglutide, and semaglutide. Weight loss, quality‐of‐life scores, and costs were estimated using clinical trials and other published literature. Endpoints included costs, quality‐adjusted life years (QALYs), and incremental cost‐effectiveness ratios (ICERs) with a willingness‐to‐pay (WTP) threshold of $100 000/QALY. Results were analysed at 1‐, 3‐, and 5‐year time horizons. Results At each of the three follow‐up periods, phentermine was the cost‐effective strategy, with ICERs of $46 258/QALY, $20 157/QALY, and $17 880/QALY after 1, 3, and 5 years, respectively. Semaglutide was the most effective strategy in the 3‐ and 5‐year time horizons, with total QALYs of 2.224 and 3.711, respectively. However, the ICERs were prohibitively high at $1 437 340/QALY after 3 years and $576 931/QALY after 5 years. Deterministic and probabilistic sensitivity analyses indicated these results were robust. Conclusions Phentermine is the cost‐effective pharmacologic weight‐loss strategy. Although semaglutide is the most effective, it is not cost‐effective because of its high price.


| INTRODUCTION
An estimated 70% of the population in the United States have overweight or obesity, a threefold increase over the last 40 years. 1 Worldwide, an estimated 650 million adults live with overweight or obesity. 2 With the large population of affected individuals, the economic costs of obesity are substantial. The cost of medical care related to obesity in adults is estimated at $85.7 billion in the United States 3 but could be as much as $209.7 billion. 4 On a global level, obesity-related complications are estimated to cost $1.2 trillion by 2025, almost half of which will be spent in the United States alone. 5 Weight reduction of as little as 5% in individuals with obesity is associated with improved health outcomes and reduced incidence of obesity-related comorbidities, including cardiovascular disease and diabetes. 6 Effective treatments and interventions are crucial but remain elusive.
Lifestyle intervention, with diet, physical activity, and behaviour modification, is the standard first-line therapy for overweight and obesity. However, adaptive physiologic responses, such as increased appetite and decreased resting metabolic rate, make it difficult to maintain weight loss through lifestyle intervention alone. 7 After initial weight loss in the first year, weight regain occurs at an average rate of 1 to 2 kg y −1 . 6,8 For this reason, individuals with a body mass index (BMI) of at least 30 kg m −2 or a BMI of at least 27 kg m −2 with weight-related comorbidities are eligible for pharmacotherapy. 7,9 The Food and Drug Administration (FDA) has approved several pharmacotherapies to treat overweight and obesity. As more agents enter the market, comparative efficacy and economic burdens are difficult to discern. Randomized, placebo-controlled trials for orlistat, lorcaserin, liraglutide, and phentermine/topiramate have shown promising results for individuals with obesity, leading to FDA approval. In each trial, the majority of participants lost 5% to 10% of their baseline weight within the first year. [10][11][12][13] Phentermine and semaglutide are not FDA approved for long-term treatment of obesity. However, both medications demonstrate efficacy and increasing use within the medical community. 5,14,15 Phentermine is the most commonly prescribed pharmacotherapy for weightloss in the United States, despite FDA approval for only short-term use (90 days) and a lack of large, long-term clinical trials. [15][16][17] In a randomized, placebo-controlled trial, individuals with overweight or obesity lost an average of 9.3% of baseline body weight after 14 weeks. 18 Once-weekly semaglutide is FDA approved only as treatment for type 2 diabetes. However, a recent phase 2, randomized, double-blind, placebo and active controlled trial with nondiabetic individuals found promising results for daily semaglutide as obesity treatment (n = 957). Results indicated that semaglutide doses of 0.2 mg d −1 or more significantly increased weight loss compared with both liraglutide (3.0 mg d −1 ) and placebo. 5 In addition, a recent randomized, placebocontrolled trial demonstrated that diabetic patients on semaglutide can sustain weight loss for at least 2 years. 19 A clinical trial comparing all available pharmacotherapies for obesity is unlikely to occur in the future for various reasons, including the high costs and large sample sizes that would be required. The purpose of this study is to compare and analyse the cost-effectiveness of six pharmacotherapies and intensive lifestyle intervention in patients with mild obesity (BMI between 30 and 35). It builds on previous cost-effectiveness analyses 20,21 by focusing exclusively on pharmacotherapy treatment for a specific population and including phentermine and semaglutide. In addition, this analysis follows patients on long-term treatment (over 1 year), in accordance with the increasing recognition of obesity as a chronic, relapsing medical disease. 22 2 | METHODS  Table 1). The therapy adherence rate was assumed to be constant for years 2 to 5. Mortality rates were estimated using BMI-specific life tables from a previous analysis on the impact of obesity on mortality (Table S1). 39 The model cycle length, or time between state transitions, was 1 month. All model inputs are listed in Table 1.

| Strategies for weight management
Patients receiving no treatment experienced slight weight gain over time, based on published literature. 24 This group served as a reference group composed of individuals not attempting any self-directed weight loss. For patients in the treatment strategies, weight change was based on data from randomized, placebo-controlled clinical trials (Table 2). In cases with more than one published clinical trial, the trial with the longest duration was selected. All pharmacotherapy clinical trials also included lifestyle modification counselling.
Most clinical trials contained data on weight loss for at least 2 years. For the model input, weight change was converted to rate of BMI change using average baseline weight and BMI values in the trial cohort (Table 1). Weight loss in the ILI strategy was based on data from the Look AHEAD study, which reported percent reduction from baseline weight over 8 years among type 2 diabetes patients receiving either ILI or diabetes support and education. 25 For the 3-year and 5year time horizons of the pharmacotherapy strategies, weight was assumed to increase linearly after the first year of pharmacotherapy.
This assumption was based on the observed trends in the SCALE, BLOOM, and SEQUEL trials for liraglutide, lorcaserin, and phentermine/topiramate, respectively. 10,28,29 For semaglutide, there were no clinical data past 1 year for a daily dose of 0.4 mg. 5 However, the SUSTAIN-6 trial followed type 2 diabetes patients on a weekly dose of 1.0 mg for 104 weeks. 19 Change in weight after the first year from this study was used to estimate weight change on daily semaglutide after the first year in the model. For patients who dropped out of a weight loss strategy, the rate of weight regain was based on data from patients in the BLOOM trial who received lorcaserin in the first year and placebo in the second year. 10 If a patient returned to baseline weight, the rate of weight gain was equivalent to patients on no treatment.

| QOL adjustments and costs
QOL was dependent on weight change. A QOL constant of 0.0056 quality-adjusted life years (QALYs) gained per BMI unit lost was used based on prior literature. 37,38 The model assumes a health care system cost perspective. Cost of no treatment was assumed to be zero. Costs of treatments were estimated from published literature ( Table 1). The cost of semaglutide was estimated from the cost of once-weekly 1.0 mg injections. 36 For all pharmacotherapy arms, the cost for two physician visits ($178) was added to the first year, to account for the two visits expected for patients beginning weight loss medication. 20 Costs of comorbidities and adverse events were not included. All costs from prior years were adjusted to 2019-year dollars using the Consumer Price Index. Both costs and utilities were discounted at a rate of 3%.

| Outcomes
Study endpoints included QALYs, total costs (US $2019), and incremental cost-effectiveness ratios (ICERs). ICERs are calculated as the  ratio of differences in costs and QALYs between a strategy and the next best alternative. A commonly used willingness-to-pay (WTP) threshold of $100 000/QALY determined cost-effectiveness. 40

| Sensitivity analyses
To Gamma distributions were used for costs, and beta distributions were used for all other parameters. One thousand Monte Carlo samples were run per strategy with cohorts of 10 000 patients. The percentage of times each strategy was cost-effective at various WTP thresholds was recorded.

| Base case results
The results of the base case analysis are given in Table 3

| PSA results
Probabilistic sensitivity analyses were performed on the model over the three time horizons. Acceptability curves are shown in Figure 3, and scatter plots of cost and effectiveness values are shown in

| DISCUSSION
The aim of this analysis was to determine cost-effectiveness among six pharmacotherapies and ILI used to treat obesity. A simulation model was used as a platform to incorporate weight loss and QOL data from clinical trials and other published literature. The modelling results found that phentermine was the cost-effective strategy over  When excluding patients with a history of cardiovascular events, a large electronic health record study found significantly greater weight loss among "off-label" phentermine users (those who take the drug longer than the FDA-approved 90 days) without any increase in risk for cardiovascular events over 3 years. 15 In addition, given the wide- programmes. 20,21 However, this study is the first cost-effectiveness analysis to directly compare six pharmacotherapies. This is also the first analysis to incorporate data from the recent clinical trial on the efficacy and safety of daily semaglutide for the treatment of obesity.
In addition, other similar analyses did not include phentermine. A variety of treatments were included in the analysis in order to reflect decision making in clinical practice, primarily for patients who have unsuccessfully attempted weight loss with lifestyle intervention.
There were limitations to this analysis that should be acknowledged. This model did not directly incorporate adverse effects or side effects of treatment. Instead, QOL was dependent solely on weight loss. This was due to insufficient data regarding quality of life and the side effects of each drug. Treatment adherence was incorporated, however, which directly impacts therapy effectiveness and is largely dependent on adverse events and side effects. In addition, since most clinical trials included data for only 1 or 2 years, changes in weight were extrapolated past the first year for the extended time analyses with the assumption that weight linearly increased. This was based on the plateau or slight increase seen in many clinical trials after about 40 weeks. It was possible for patients to remain on treatment for all 5 years, which is uncommon and, in some cases, not recommended for some pharmacotherapies, particularly phentermine. In addition, many patients take medications intermittently, which was not considered in this modelling analysis. However, longer term continuous treatment regimens are becoming more common in accordance with the growing understanding of obesity as a chronic disease. 15 Extensive sensitivity analyses were performed to evaluate the uncertainty resulting from model assumptions and indicated that the results were consistent despite changes in the parameters.
In summary, this modelling analysis found that phentermine is the cost-effective pharmacotherapy currently on the market. This highlights the influence of drug cost and the need for further research into