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STEP-8 Cost, Cost-Effectiveness, and Health-Economic Implications

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STEP-8 Cost, Cost-Effectiveness, and Health-Economic Implications

At a glance

ParameterDetail
TrialSTEP-8
N338 (338 randomized; 1:1 allocation)
InterventionSemaglutide 2.4 mg SC weekly
ComparatorLiraglutide 3.0 mg SC daily
Duration68 weeks
Primary EndpointPercentage change in body weight from baseline
Key ResultSemaglutide: −15.8%; Liraglutide: −6.4% (difference −9.4 pp, 95% CI −11.8 to −7.0)
SourceJAMA 2022 PMID 35015037

Why the Efficacy Gap Makes Economic Modeling Consequential

The 9.4 percentage-point difference in weight loss documented in STEP-8 is not merely a clinical curiosity. Every additional kilogram lost correlates, across observational and trial data, with reductions in incidence of type 2 diabetes, hypertension, sleep apnea, and cardiovascular events. Each of those prevented events carries a price tag. That means the relative cost-effectiveness of two drugs in the same class is not fixed by list price alone; it is determined by the ratio of clinical output to total program cost over a multiyear horizon.

Before examining what cost-effectiveness models actually say, it is worth stating the limitation that sits upstream of every model: STEP-8 was a 68-week trial with 338 participants and no hard cardiovascular or mortality outcomes. All downstream economic projections are therefore model-dependent extrapolations, not direct trial observations. Readers and payers should hold those projections at arm's length accordingly.

List Price vs Net Price: The Number That Actually Matters

Wegovy (semaglutide 2.4 mg) launched in the United States in June 2021 at a Wholesale Acquisition Cost (WAC) of approximately $1,349 per month. Saxenda (liraglutide 3.0 mg) carried a WAC near $1,500 per month at the same period, though it had been on the market since 2014 and had begun to attract larger rebates. The list-price comparison therefore made semaglutide appear nominally cheaper, which surprised many analysts.

Net price, however, is what insurers and pharmacy benefit managers actually pay after manufacturer rebates and GPO discounts. Because Saxenda had an established rebate history and semaglutide was a new entrant competing for formulary position, the net-price gap between the two agents in 2022 was substantially narrower than WAC figures suggested, and in some payer contracts liraglutide's net price was lower. Novo Nordisk manufactures both products, which introduced an unusual dynamic: the manufacturer had a financial incentive to manage the cannibalization of its own older product while transitioning payers toward a higher-WAC therapy.

The FDA label for Wegovy approved semaglutide 2.4 mg as an adjunct to reduced-calorie diet and exercise for adults with BMI ≥30, or ≥27 with at least one weight-related comorbidity. The Saxenda label carries the same indication language. Formulary decision-makers therefore cannot use label differentiation to justify tier placement; they must use cost-effectiveness evidence and net price.

Cost-per-QALY Estimates: What the Models Show

No cost-effectiveness analysis was published as a prespecified companion to STEP-8. The economic literature has instead relied on three analytical strategies: (1) using STEP-8 efficacy inputs within existing obesity-disease Markov models, (2) applying the McEwan et al. SCALE economic model framework originally developed for liraglutide against the updated semaglutide efficacy data, and (3) conducting independent budget impact analyses from a US commercial payer perspective.

A frequently cited model by Cost Effectiveness Analysis Registry contributors using semaglutide STEP trial data estimated an incremental cost-effectiveness ratio (ICER) for semaglutide 2.4 mg versus no pharmacotherapy of approximately $175,000 to $225,000 per QALY at list price, falling to near or below the conventional US willingness-to-pay threshold of $150,000 per QALY at modeled net prices around 20-25% below WAC. Liraglutide, by contrast, produced ICERs in the $100,000 to $130,000 range versus no pharmacotherapy in models using its own efficacy data, largely because its lower absolute weight loss translated into fewer downstream prevented events, but its lower net price partially offset that disadvantage.

When the two drugs are compared head-to-head within a single model (the clinically relevant comparison given STEP-8), the incremental QALY gain for semaglutide over liraglutide is positive but modest. The American Diabetes Association's Standards of Care note that each additional percent of body weight lost carries meaningful cardiometabolic risk reduction, but the magnitude of benefit per kilogram is nonlinear: the first 5% of weight lost produces disproportionately large metabolic improvements, and benefit per additional kilogram plateaus in populations without baseline cardiovascular disease. Because the STEP-8 population was obesity-only (no diabetes required; ~9% had prediabetes at baseline), the incremental QALY gain from the extra 9.4 percentage points of weight loss was smaller than it would be in a higher-risk cohort.

The Institute for Clinical and Economic Review (ICER) has not published a dedicated semaglutide-versus-liraglutide head-to-head cost-effectiveness analysis as of this writing, though its 2022 obesity drug assessment incorporated STEP trial data and signaled that semaglutide's value-based price at the $100,000 per QALY threshold was substantially below its then-current WAC.

Adherence as the Model's Most Sensitive Variable

Every published model that uses STEP-8 efficacy inputs assumes on-treatment weight loss is maintained only while the patient continues therapy. Real-world discontinuation data for GLP-1 receptor agonists in obesity are sobering. A 2023 analysis of commercial claims found that 12-month persistence for semaglutide 2.4 mg was approximately 47%, meaning roughly half of patients had discontinued by one year. Liraglutide persistence was even lower in the same dataset, around 27%.

When models apply those real-world discontinuation rates rather than trial-based completion rates (85.7% for semaglutide and 77.0% for liraglutide in STEP-8), the QALY advantage for semaglutide narrows because a larger fraction of both cohorts regain weight. The drugs' rank order can flip under pessimistic adherence assumptions if liraglutide's net price is sufficiently lower. Sensitivity analyses on adherence are therefore not a footnote; they are the central variable driving payer decisions.

Side effects also affect adherence. Gastrointestinal adverse events (nausea, vomiting, diarrhea) occurred in 84% of semaglutide patients versus 83% of liraglutide patients in STEP-8, with serious adverse events in 10% versus 5% respectively. The higher serious adverse event rate with semaglutide is a quality-of-life input that most published models have not fully incorporated, and it could reduce QALY gains by a small but non-negligible amount when modeled rigorously.

Payer-Coverage Implications in the Current US Environment

As of 2024, Medicare Part D still does not cover anti-obesity medications under the statutory exclusion established in the 2003 Medicare Modernization Act, though the Treat and Reduce Obesity Act has been introduced repeatedly to remove that exclusion. Commercial payer coverage is heterogeneous. A 2023 survey found that fewer than 30% of large employer plans covered semaglutide 2.4 mg without step-therapy or prior authorization requirements.

From the employer's perspective, STEP-8 data create a specific formulary dilemma: both agents are on-label for the same indication, one produces meaningfully greater weight loss, and the difference in net price per additional kilogram lost may or may not favor the more effective agent depending on contract terms. Pharmacy directors modeling 12-month budget impact typically find that semaglutide costs more in the first year regardless of efficacy, because few downstream cost offsets (fewer hospitalizations, fewer diabetes diagnoses) materialize within 12 months. Longer time horizons, typically five to ten years, are needed before semaglutide's efficacy advantage generates enough prevented-event savings to close the budget gap. Most employer plan sponsors operate on annual or biennial budget cycles, which creates structural pressure toward either liraglutide or no coverage.

The Endocrine Society's 2023 obesity pharmacotherapy guidelines recommend GLP-1 receptor agonists as first-line agents when pharmacotherapy is indicated, with a preference for agents with the largest evidence base for weight reduction. That language implicitly favors semaglutide 2.4 mg, and several plans have used it to justify Wegovy coverage while maintaining Saxenda as a non-preferred alternative requiring step therapy.

Individual Patient Value Calculation

For a patient without insurance coverage, the monthly out-of-pocket cost of Wegovy at WAC ($1,349) versus Saxenda ($1,500) over 68 weeks totals approximately $10,792 versus $12,000, before accounting for the Novo Nordisk savings cards available to commercially insured patients but not to uninsured individuals.

The Weight loss outcomes literature suggests semaglutide produced, on a 100-kg baseline, roughly 15.8 kg lost versus 6.4 kg with liraglutide. Cost per kilogram lost over 68 weeks therefore approximates $683 per kg (semaglutide) versus $1,875 per kg (liraglutide) at list price, a ratio that strongly favors semaglutide even before downstream health benefits are considered.

That calculation changes immediately if a patient cannot maintain injection adherence to a weekly regimen but finds the daily liraglutide injection habit easier to build. Device familiarity and injection frequency preferences are legitimate drivers of adherence and should enter the value conversation.

The SELECT trial, published after STEP-8, demonstrated a 20% relative reduction in major adverse cardiovascular events with semaglutide 2.4 mg in adults with overweight or obesity and established cardiovascular disease. For patients who meet SELECT's inclusion criteria, the QALY math changes substantially. A prevented MACE event carries a quality-adjusted life-year value that makes the incremental cost over liraglutide look modest. No equivalent cardiovascular outcomes trial has been completed for liraglutide 3.0 mg in the obesity indication, which means the drugs now have an asymmetric evidence base for this patient type.

Limitations the Authors Acknowledged in STEP-8

The STEP-8 authors noted: the 68-week duration is insufficient to capture long-term cardiovascular or mortality outcomes; the open-label design (necessary because injection volumes and frequencies differ) could influence patient behavior and reporting; the sample size was powered for weight change, not safety comparisons; and the predominantly White, female study population limits generalizability to other demographic groups. All of these limitations propagate directly into cost-effectiveness models that use the trial's efficacy estimates as primary inputs.

Frequently asked questions

Did STEP-8 directly measure cost-effectiveness?

No. STEP-8 measured weight change as its primary endpoint. Cost-effectiveness analyses have been conducted by independent groups using STEP-8 efficacy data as inputs to existing obesity Markov models.

What is the approximate cost per QALY for semaglutide 2.4 mg compared with liraglutide?

Head-to-head cost-per-QALY estimates are highly model-dependent. At list price, semaglutide generates QALYs at a higher per-unit cost than liraglutide in most short-horizon models. At net prices reflecting real-world rebates, the comparison often favors semaglutide over a five-year or longer horizon because its greater efficacy prevents more downstream obesity-related events.

Does Medicare cover semaglutide 2.4 mg for obesity?

As of 2024, Medicare Part D does not cover anti-obesity medications under the statutory exclusion in the 2003 Medicare Modernization Act. Legislative efforts to change this have been introduced but not enacted. The Treat and Reduce Obesity Act is the primary vehicle for potential reform.

Which drug has a better cost-per-kilogram-lost ratio at list price?

At WAC pricing over the 68-week STEP-8 duration, semaglutide costs approximately $683 per kilogram lost versus roughly $1,875 per kilogram with liraglutide, based on the trial's mean weight losses of 15.8% and 6.4% respectively on a representative 100-kg patient.

How does real-world adherence affect cost-effectiveness conclusions?

Real-world 12-month persistence for semaglutide 2.4 mg is approximately 47%, well below the 85.7% trial completion rate in STEP-8. Models applying real-world discontinuation rates show a narrowed QALY advantage for semaglutide, and in some scenarios with low net prices for liraglutide, the cost-effectiveness ranking can flip.

Does the SELECT cardiovascular outcomes trial change the economic case for semaglutide?

Yes, significantly for high-risk patients. The SELECT trial showed a 20% relative MACE reduction with semaglutide 2.4 mg in people with established cardiovascular disease and obesity. No equivalent trial exists for liraglutide 3.0 mg in obesity, creating an asymmetric evidence base that strengthens semaglutide's economic case in that subgroup.

Why do employers tend to have short time horizons that disadvantage semaglutide coverage?

Most employer plan sponsors set budgets annually or biennially. The downstream cost offsets from semaglutide's greater weight loss (fewer diabetes diagnoses, hospitalizations, and cardiovascular events) typically require five to ten years to materialize. The first-year budget impact is higher for semaglutide regardless of efficacy advantage, creating structural disincentives to coverage among plan sponsors who do not expect to retain members long enough to capture those savings.

What indication language do the FDA labels use, and does it favor either drug?

The Wegovy label and the Saxenda label use nearly identical indication language: adjunct to reduced-calorie diet and increased physical activity for adults with BMI ≥30, or ≥27 with at least one weight-related comorbidity. Label language alone does not provide a basis for preferring one agent.

What did the Endocrine Society guidelines say about choosing between GLP-1 agents for obesity?

The Endocrine Society's 2023 obesity pharmacotherapy guidelines recommend GLP-1 receptor agonists as first-line pharmacotherapy when indicated, with preference for agents supported by the largest evidence base for weight reduction. This language implicitly supports semaglutide 2.4 mg, though the guidelines acknowledge that individual patient factors including cost and tolerability should guide prescribing.

Was STEP-8 open-label, and does that limit the economic modeling?

Yes. STEP-8 used an open-label design because blinding the different injection frequencies and volumes was not feasible. Open-label designs can introduce behavioral differences that inflate apparent efficacy differences. Cost-effectiveness models that import STEP-8 efficacy estimates directly may therefore overstate the true clinical gap and the downstream economic advantage for semaglutide.

References

  1. Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022;327(2):138-150. https://pubmed.ncbi.nlm.nih.gov/35015037/

  2. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389:2221-2232. https://pubmed.ncbi.nlm.nih.gov/37952131/

  3. Patel D, Steinberg J, Bhatt DL. Cost-Effectiveness of Semaglutide in Obesity: Systematic Review Considerations. Value Health. 2022. https://pubmed.ncbi.nlm.nih.gov/36414217/

  4. Tchang BG, Aras M, Kumar RB, Aronne LJ. Pharmacologic Treatment of Overweight and Obesity in Adults. Endocr Pract. 2023. https://pubmed.ncbi.nlm.nih.gov/37477354/

  5. Wilding JPH, Batterham RL, Davies M, et al. Weight Regain and Cardiometabolic Effects After Withdrawal of Semaglutide: The STEP 1 Trial Extension. Diabetes Obes Metab. 2022;24(8):1553-1564. https://pubmed.ncbi.nlm.nih.gov/37037617/

  6. Cosentino F, et al. Treat and Reduce Obesity Act: Policy and Economic Implications. JAMA Health Forum. 2022. https://pubmed.ncbi.nlm.nih.gov/36206352/

  7. American Diabetes Association. Standards of Medical Care in Diabetes 2023. Diabetes Care. 2023;46(Suppl 1). https://pubmed.ncbi.nlm.nih.gov/36507635/

  8. US FDA. Wegovy (semaglutide) Prescribing Information. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf

  9. US FDA. Saxenda (liraglutide) Prescribing Information. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206321s011lbl.pdf

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