Obesity is a common chronic disease, affecting approximately 40% of adults in the United States.1 It is associated with an increased risk of other chronic conditions, including type 2 diabetes (T2D), hypertension, liver disease, obstructive sleep apnea, cancer, and cardiovascular (CV) disease. More than half of the adults living with obesity have hypertension, and nearly one-quarter have diabetes.1 Thus, the economic burden of obesity on both patients and the health system is high, with an estimated $172 billion in medical costs annually attributed to the disease.2
Treatment for obesity is often targeted toward weight loss as it generally leads to improvements in metabolic markers, depression, and quality of life, as well as a decreased risk of developing obesity-related complications and death. Lifestyle modifications generally result in a 5% to 10% loss of body weight; however, many people do not achieve this level of weight loss, and most are unable to sustain weight loss over time.3,4 Because most people do not achieve the desired weight loss with lifestyle modification, medications and/or bariatric surgery are often considered.5 The emergence of medications like semaglutide that target the glucagon-like peptide-1 (GLP-1) receptor and tirzepatide, a dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist, has dramatically altered the landscape of obesity treatment. Both semaglutide and tirzepatide are available as weekly injections; semaglutide is also available as a daily oral pill.
The Institute for Clinical and Economic Review (ICER) conducted a systematic literature review and cost-effectiveness analysis to evaluate the clinical and economic outcomes of semaglutide and tirzepatide in individuals with obesity and without diabetes. This article summarizes our findings and highlights the key policy recommendations discussed at the New England Comparative Effectiveness Public Advisory Council (NE CEPAC) public meeting on November 13, 2025. The full report is available on ICER’s website (https://icer.org/assessment/obesity-2025/)
Summary of Findings
CLINICAL EFFECTIVENESS
We evaluated the evidence on the clinical effectiveness of semaglutide (injectable and oral) and tirzepatide in adults with obesity or overweight and at least 1 weight-related comorbid condition, without diabetes, who are actively seeking medical management for weight loss. Each intervention was evaluated in combination with lifestyle modification compared with lifestyle intervention alone. In addition, we sought to compare the interventions.
There were 6 randomized controlled trials (RCTs) that informed our evaluation on injectable semaglutide.6–11 A meta-analysis of 4 of the trials that evaluated weight loss showed a greater weight loss with injectable semaglutide plus lifestyle intervention compared with placebo plus lifestyle intervention at 68 weeks (mean difference: −13.1%; 95% CI = −15 to −11.3).6–9 In addition, in adults with obesity and known CV disease, treatment with injectable semaglutide led to a 20% risk reduction (hazard ratio [HR] = 0.80; 95% CI = 0.72 to 0.90) in major adverse cardiovascular event (MACE) and all-cause mortality (HR = 0.81; 95% CI = 0.71 to 0.93) compared with treatment with placebo.11
Data to inform our evaluation of oral semaglutide came from 1 key trial. The trial showed a greater reduction in weight with oral semaglutide plus lifestyle intervention vs placebo plus lifestyle intervention (percentage reductions: 13.6% vs 2.2%; mean difference: −11.4%; 95% CI = −13.9 to −9) at week 64.12 There were no clinical trials evaluating the cardiovascular outcome of oral semaglutide in the population of interest, although we identified 2 trials evaluating the CV benefit of a lower dose of oral semaglutide among adults with T2D with established CV disease or at high risk for CV events.13,14 A meta-analysis of the 2 trials showed a 14% reduction in MACE (relative risk = 0.86; 95% CI = 0.78 to 0.95) with oral semaglutide compared with placebo.
For tirzepatide, we identified 2 placebo-controlled RCTs. Treatment with tirzepatide plus lifestyle intervention resulted in greater percentage reductions in weight compared with placebo plus lifestyle intervention at week 72 (mean differences: −17.8% [95% CI = −19.3 to −16.3] and −20.8% [95% CI = −23.2 to −18.5]).15,16 There were no clinical trials evaluating tirzepatide in patients with obesity and without diabetes. However, we identified 1 trial that evaluated tirzepatide vs dulaglutide in patients with T2D and known atherosclerotic CV disease. The trial showed that participants treated with tirzepatide had an 8% reduction (HR = 0.92) in the risk of MACE and 16% reduction (HR = 0.84; 95% CI = 0.75 to 0.94) in all-cause mortality compared with the dulaglutide group.17
We identified 1 head-to-head trial comparing tirzepatide to semaglutide. Participants treated with tirzepatide lost almost 7% more weight than those treated with semaglutide (% reduction: −20.2% vs −13.7%).18 However, there are no head-to-head trials comparing the interventions on CV outcomes.
All 3 drugs generally improved health-related quality of life, as well as metabolic risk factors such as blood pressure, blood glucose, and lipids; however, stopping the drugs was associated with weight regain and regression of improvement in metabolic risk factors.
The most common harms of both semaglutide and tirzepatide are gastrointestinal side effects, with approximately 75% of trial participants taking either injectable or oral semaglutide reporting gastrointestinal side effects.6–9,12 For tirzepatide, 20% to 40% of participants reported nausea, diarrhea, or constipation in clinical trials.15,16 However, serious adverse events were uncommon, occurring in 3% to 10% of participants in the semaglutide trials and 4% to 6% in the tirzepatide trials. Finally, discontinuation due to adverse events was also less than 10% for all 3 drugs. Additional details are available in the full report: https://icer.org/wp-content/uploads/2025/12/ICER_Obesity_Final-Report_For-Publication_121625-1.pdf.
LIMITATIONS OF CLINICAL EVIDENCE
Although we have high certainty that all 3 treatments offer a substantial net benefit over lifestyle modification, there is less certainty about the relative effects of the drugs to each other, particularly for outcomes beyond weight loss (eg, CV outcome). Injectable semaglutide showed CV benefits in people with obesity and known CV disease; whether this benefit extends to primary prevention is unknown, but it is reasonable to assume, given the improvements in CV risk factors. Whether this CV risk reduction extends to oral semaglutide 25 mg is not clear, as this dose results in less weight loss than the injectable form, and a lower dose (14 mg) resulted in smaller CV risk reduction in a diabetes population. The trial showing benefit from tirzepatide on CV outcomes enrolled people with T2D and existing CV disease, and the comparator was another GLP-1 RA (dulaglutide), making comparisons with semaglutide indirect. Additionally, many of the trials related to obesity-related complications were done in a population with T2D, and thus, efficacy in nondiabetic populations is less clear. Lack of long-term benefits and harms data from either clinical trials or observational studies is another key limitation because of concerns about weight maintenance, potential loss of muscle mass, and risk of pancreatitis.
LONG-TERM COST-EFFECTIVENESS
We developed a de novo decision analytic Markov cohort model to compare the cost-effectiveness of the 3 obesity treatments (injectable semaglutide, oral semaglutide, or tirzepatide) added to lifestyle modification vs lifestyle modification alone for the treatment of obesity in patients without diabetes over a lifetime horizon. The model was primarily designed to simulate the treatment’s impact on weight and on preventing the onset of key obesity-related outcomes and thus consisted of health states representing 1 or more combinations of obesity-related outcomes (CV disease and events, T2D, end-stage kidney disease, cirrhosis, hip or knee replacement, and obstructive sleep apnea). Patients entered the model in a nondiabetic health state and could develop 1 or more combinations of obesity-related outcomes, including T2D, over time. Multiple outcomes could develop within a single cycle, and patients could die from any health state. Within the CV disease health state, patient distribution across specific subtypes of CV disease was tracked over time, using the following categories: post–myocardial infarction (MI), post-stroke, post-MI and post-stroke, heart failure (HF) post-MI, post-stroke and HF post-MI, and other CV disease (including other forms of HF, peripheral artery disease, angina, and transient ischemic attack).
The model made several assumptions, including that weight-lowering medications may have direct effects on preventing obesity-related outcomes, independent of weight loss–mediated benefits. Also, treatment discontinuation rates were based on the trial’s intention-to-treat population, and those remaining on treatment during the trial period were assumed to remain on therapy for the duration of the model. Key inputs were derived from multiple sources, including ICER meta-analysis, ICER’s prior report on obesity, relevant clinical trials, and existing literature. In addition to the base-case analyses from a health sector perspective, we conducted 6 scenario analyses, including a modified societal perspective analysis, alternative assumptions or estimates (eg, exclusion of unrelated health care costs), and heterogeneity based on the baseline body mass index (BMI). The annual net prices for injectable semaglutide ($6,830) and tirzepatide ($7,973) were derived from SSR Health as of Q1 2025, as its estimates reflect aggregated net prices that account for the use of direct-to-patient options available through NovoCare and LillyDirect. We assumed the price of oral semaglutide to be the same as that of injectable semaglutide because oral semaglutide was not approved at the time of our ICER report. Further details about the model, key assumptions, and inputs can be found in the full report: https://icer.org/wp-content/uploads/2025/12/ICER_Obesity_Final-Report_For-Publication_121625-1.pdf.
Our analyses showed that treatment with injectable semaglutide, oral semaglutide, and tirzepatide resulted in increased quality-adjusted life years (QALYs), equal-value life-years (evLYs), and life-years and led to fewer CV events compared with treatment with lifestyle modifications alone, with tirzepatide treatment resulting in the greatest gains (Table 1). The incremental cost-effectiveness ratios for each drug are listed in Table 2. All drugs were cost-effective at the $100,000 per QALY and evLY gained thresholds.
TABLE 1.
Base-Case Results for the Interventions and Lifestyle Modification
| Treatment | Intervention acquisition costs | Total costs | Number of stroke or MI events (per 100) | QALYs | evLYs | Life -years |
|---|---|---|---|---|---|---|
| Injectable semaglutide | $132,229 | $447,925 | 47 | 16.79 | 16.81 | 20.39 |
| Oral semaglutide | $132,475 | $449,980 | 51 | 16.68 | 16.70 | 20.35 |
| Tirzepatide | $158,493 | $459,232 | 45 | 17.19 | 17.21 | 20.49 |
| Lifestyle modification | $9,036 | $370,644 | 69 | 15.63 | 15.63 | 20.01 |
evLY = equal-value life-year; MI = myocardial infarction; QALY = quality-adjusted life-year.
TABLE 2.
Incremental Cost-Effectiveness Ratios for the Base Case vs Lifestyle Modification
| Treatment | Cost per QALY gained | Cost per evLY gained | Cost per LY gained | Cost per MI or stroke avoided |
|---|---|---|---|---|
| Injectable semaglutide | $66,355 | $65,280 | $202,949 | $669,832 |
| Oral semaglutide | $75,456 | $74,143 | $233,969 | $861,284 |
| Tirzepatide | $56,622 | $56,076 | $184,598 | $709,088 |
evLY = equal-value life-year; MI = myocardial infarction; QALY = quality-adjusted life-year.
LIMITATIONS OF THE COST-EFFECTIVENESS MODEL
Obesity trials are limited to only 2 to 3 years of follow-up. As such, there was uncertainty around long-term treatment effects beyond the trial period because data are not yet available on whether weight loss, as well as direct treatment effects on diabetes and CV diseases observed in the trials, are maintained long term. Data on the direct treatment effect of oral semaglutide on CV outcomes came from trials that included individuals with T2D, meaning there could be uncertainty regarding the generalizability of these findings to the obesity population without diabetes. Direct treatment effects for outcomes such as end-stage kidney disease and cirrhosis were not included in the model owing to data limitations. There were also additional uncertainties related to net drug prices, real-world treatment patterns, and outcomes associated with real-world treatment discontinuation and adherence.
Policy Discussion
The NE CEPAC is one of the independent appraisal committees convened by ICER to engage in the public deliberation of the evidence on clinical and cost-effectiveness of health care interventions. The NE CEPAC is composed of medical evidence experts, including clinicians, methodologists, and patient advocates. The ICER report on semaglutide (injectable and oral) and tirzepatide for obesity was the subject of an NE CEPAC meeting on November 13, 2025. Following the discussion, the NE CEPAC panel members deliberated on key questions raised by ICER’s report.
The results of their votes on the clinical evidence were as follows. (1) The panel voted unanimously (14 to 0) that the evidence is adequate to demonstrate that the net health benefit of injectable semaglutide, oral semaglutide, and tirzepatide added to lifestyle modification is greater than that of lifestyle modification alone for the treatment of obesity. (2) The panel voted 13 to 1 that the current evidence is not adequate to distinguish a difference in net health benefit between tirzepatide and injectable semaglutide. (3) The panel voted 9 to 5 that the current evidence is not adequate to distinguish a difference in net health benefit between injectable semaglutide and oral semaglutide.
The NE CEPAC also voted on “benefits beyond health and special ethical perspectives” as part of a process intended to signal to policymakers whether there are important considerations when making judgments about the long-term value for money that are not adequately captured in analyses of clinical and/or cost-effectiveness. The results for these votes are shown in Tables 3 and 4.
TABLE 3.
New England CEPAC Votes on Benefits Beyond Health and Special Ethical Priorities—Condition Specific
| Benefits beyond health and special ethical priorities | Strongly disagree | Disagree | Neutral | Agree | Strongly agree |
|---|---|---|---|---|---|
| There is substantial unmet need despite currently available treatments. | 0 | 0 | 2 | 5 | 7 |
| This condition is of substantial relevance for people from a health/ethnic group that have not been equitably served by the health care system. | 0 | 0 | 1 | 4 | 9 |
CEPAC = Comparative Effectiveness Public Advisory Council.
TABLE 4.
New England CEPAC Votes on Benefits Beyond Health and Special Ethical Priorities—Treatment Specific
| Benefits beyond health and special ethical priorities | Strongly disagree | Disagree | Neutral | Agree | Strongly agree |
|---|---|---|---|---|---|
| Injectable semaglutide, compared with lifestyle modification alone, is likely to produce substantial improvement in caregivers’ quality of life and/or ability to pursue their own education, work, and family life. | 1 | 3 | 3 | 7 | 0 |
| Oral semaglutide, compared with lifestyle modification alone, is likely to produce substantial improvement in caregivers’ quality of life and/or ability to pursue their own education, work, and family life. | 1 | 3 | 6 | 4 | 0 |
| Tirzepatide, compared with lifestyle modification alone, is likely to produce substantial improvement in caregivers’ quality of life and/or ability to pursue their own education, work, and family life. | 1 | 3 | 5 | 5 | 0 |
| Oral semaglutide offers a substantial opportunity to improve access to effective treatment by means of its mechanism of action or method of delivery. | 0 | 1 | 2 | 10 | 1 |
CEPAC = Comparative Effectiveness Public Advisory Council.
The culminating vote of the CEPAC panel, intended to reflect its integration of the relevant elements of the value assessment framework, was on the “long-term value for money.” The majority of the panel voted that injectable semaglutide (12 to 2), oral semaglutide (12 to 2), and tirzepatide (13 to 1) offer high long-term value for money at the current or assumed pricing.
Following the discussion of the evidence and the votes, the meeting concluded with a policy roundtable in which 2 clinical experts, 2 patient advocates, 2 payers, and 2 representatives from the manufacturers discussed how best to translate the evidence and additional considerations into clinical practice and pricing and insurance coverage policies. The full set of policy recommendations can be found here: https://icer.org/wp-content/uploads/2025/12/ICER_Obesity_Policy-Recommendations-Document_For-Publication_121625.pdf.
KEY POLICY RECOMMENDATIONS
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1.
All stakeholders should take steps to promote culturally sensitive, comprehensive obesity care to all patients without stigma or bias, including promoting greater awareness throughout the health care system of obesity as a chronic disease requiring lifelong treatment, advocating for an adequate workforce to deliver obesity care, and provision of culturally appropriate nutrition and psychological support.
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2.
Payers should ensure that cost-sharing and coverage policies do not further exacerbate treatment disparities through high out-of-pocket cost burdens or onerous clinical eligibility criteria and, in light of access and affordability concerns, should work with other stakeholders (eg, manufacturers, plan sponsors, clinicians, patient groups) to find innovative ways to increase access to comprehensive obesity care.
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3.
According to ICER’s Fair Access criteria, narrowing coverage for a fairly priced drug is reasonable if the population size is large, and broad coverage would create substantial increases in short-term insurance premiums, and waiting for treatment will not cause significant irremediable harm. The GLP-1 RA and GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist classes of drugs fit these criteria—there is a large eligible population for these treatments, and currently less than one-quarter of overweight adults or those living with obesity are taking semaglutide or tirzepatide. ICER estimates that less than 1% of the eligible population can be treated without exceeding ICER’s budget threshold, even though these drugs are fairly priced. Thus, payers may temporarily seek to narrow coverage, with expansion of coverage as prices are lowered or through implementation of innovative payment schemes (eg, performance agreements, subscription models, volume-based rebate agreements)
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4.
The following are some considerations for prior authorization.
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Clinical eligibility criteria: Payers could follow the example of the proposed criteria for Medicare coverage: (1) BMI greater than or equal to 27 with prediabetes or established CV disease; (2) BMI greater than or equal to 30 with uncontrolled hypertension, kidney disease, or heart failure; (3) BMI greater than or equal to 35. However, as the evidence evolves, payers should have a mechanism in place to rapidly update clinical eligibility criteria to expand coverage to new populations.
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Duration of coverage and renewal criteria: Initial coverage will likely be for a period of 12 months, which is long enough for dose titration, assessment of side effects, and assessment of efficacy. Payers should use a patient’s starting weight, not current weight, as the basis for judging whether further treatment is necessary. Clinical trial data demonstrate a high likelihood of weight regain after discontinuation in most patients.
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Provider restrictions: No provider restrictions.
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5.
Although payers may wish to employ step therapy, there is no justification for payers to make patients retry weight loss programs or medications that they have previously tried and that have failed them. In addition, payers may opt to have 1 drug from the newer GLP-1 RA class as the preferred formulary option.
Disclosures
Drs Rind, Fahim, Richardson, Agboola, Lee, and Lin report grants from Arnold Ventures and The Peterson Center on Healthcare, during the conduct of the study; and other from Abbott, AHIP, Alnylam, Anthem, AstraZeneca, Bayer Healthcare, Blue Shield of CA, Boehringer-Ingelheim, CRISPR Therapeutics, CVS, Eisai, Express Scripts, Elevance Health, GSK, Health Care Service Corporation, Humana, Kaiser Permanente, Karuna Therapeutics, LEO Pharma, Mallinckrodt, Merck, Novartis, Novo Nordisk, National Pharmaceutical Council, Otsuka, Pfizer, Premera Blue Cross, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, United Healthcare, Alliance of Community Health Plans, Blue Cross Blue Shield of MA, CALPERS, Centene Pharmacy Solutions, Chiesi USA, Inc, Point32Health, and Ventegra, outside the submitted work.
Acknowledgments
The authors thank Finn Raymond, Marie Phillips, Anna Geiger, Grace Ham, and Becca Piltch for their contributions to this report.
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