Mepolizumab Edges Out Dupilumab in Head-to-Head Real-World Asthma Biologic Showdown Among Older Medicare Patients

For millions of people with asthma who continue to suffer flare-ups despite using standard inhaler therapies, the arrival of biologic drugs has transformed what control over the disease can look like. Yet a stubborn question has lingered in clinics and payer offices alike: when a patient qualifies for more than one of these expensive injectable therapies, which one actually keeps them out of the hospital? A new real-world study published in Advances in Therapy offers one of the most direct answers to date, comparing mepolizumab and dupilumab head to head in a population that randomized clinical trials have largely overlooked—older, medically complex adults covered by Medicare fee-for-service.

The research team, led by investigators affiliated with Analysis Group and GSK, mined the Komodo Research Database, a vast repository containing more than 65 billion de-identified clinical, pharmacy, and laboratory encounters for over 238 million insured Americans. From records spanning January 2018 through May 2025, they identified 2,273 Medicare fee-for-service beneficiaries with asthma who started either mepolizumab, an antibody that blocks interleukin-5, or dupilumab, which targets the interleukin-4 receptor alpha subunit, on or after January 2019. The mepolizumab cohort numbered 1,055 patients with a mean age of 70.1 years, while 1,218 patients with a mean age of 67.4 years began dupilumab. Roughly three-quarters of each group were women, and nearly all were using maintenance controller and rescue inhaler medications before starting their biologic.

These two drugs attack different nodes of the type 2 inflammatory circuitry that drives many cases of severe asthma. Mepolizumab, approved in 2015, neutralizes interleukin-5, the signaling molecule that recruits and sustains eosinophils, the white blood cells central to eosinophilic asthma. Dupilumab, approved for asthma in 2018, intercepts interleukin-4 and interleukin-13 signaling through the shared IL-4Rα receptor, dampening a broader allergic inflammatory program. Because both agents carry guideline-supported indications for eosinophilic or type 2 asthma, many patients are eligible for either one, yet no head-to-head randomized trial has ever been conducted. That gap has left clinicians to make consequential prescribing decisions with surprisingly little direct comparative evidence, particularly for the Medicare population, which consists primarily of older adults and people with disabilities.

Methodologically, the study leaned on a statistical technique called overlap weighting, built on a propensity score model that predicted each patient’s likelihood of starting mepolizumab versus dupilumab based on demographics, healthcare utilization, comorbidities, medication use, and markers of asthma severity such as prior exacerbation rates and severe asthma diagnoses. Overlap weighting emphasizes patients whose characteristics make them plausible candidates for either drug, effectively simulating a randomized comparison within the observed data. After weighting, all measured baseline differences between the cohorts fell below the 10 percent standardized-difference threshold that signals meaningful imbalance—a critical safeguard, since 78 percent of mepolizumab initiators carried a severe asthma diagnosis before weighting, compared with just 52.2 percent of dupilumab initiators, a pattern that could otherwise have biased results against the older drug.

The primary outcome was the rate of asthma-related hospitalizations while patients remained on treatment, expressed as events per patient-year and assessed for non-inferiority using a pre-specified fixed-margin approach with the margin set at 1.10. In the overall weighted population, mepolizumab patients experienced 0.077 hospitalizations per patient-year versus 0.108 for dupilumab patients—a rate ratio of 0.71 with a 95 percent confidence interval of 0.46 to 1.08. That figure comfortably met the non-inferiority threshold, establishing that mepolizumab was at least as effective as dupilumab at preventing the most severe asthma outcomes, even if the confidence interval did not cross into formal statistical superiority.

The picture sharpened considerably when the researchers isolated a subgroup of patients who stayed adherent to their index biologic for at least six months, defined as having no treatment gap exceeding two consecutive doses and receiving more than half of the expected doses. Among 623 adherent mepolizumab patients and 542 adherent dupilumab patients, the weighted hospitalization rates fell to 0.046 and 0.086 per patient-year respectively. Here mepolizumab achieved outright statistical superiority, with a 46 percent lower hospitalization rate (rate ratio 0.54, 95 percent CI 0.30 to 0.99, p = 0.047). For a population in which asthma exacerbations requiring inpatient care account for a substantial share of the enormous direct costs of uncontrolled asthma, that difference carries both clinical and economic weight.

Exacerbations told a similar story. In the overall population, mepolizumab was associated with a statistically significant 15 percent lower rate of asthma exacerbations than dupilumab (0.915 versus 1.082 events per patient-year; rate ratio 0.85, 95 percent CI 0.72 to 1.00, p = 0.047). In the adherent subgroup, the direction remained favorable for mepolizumab—an 18 percent lower rate—though the confidence interval crossed unity (rate ratio 0.82, 95 percent CI 0.63 to 1.05, p = 0.116), so superiority was not formally established there. The authors note that these results diverge from several prior claims-based studies, which generally favored dupilumab for exacerbation reduction, and they attribute the discrepancy to differences in data sources, patient populations, and analytic frameworks rather than to inadequate confounding control in earlier work.

One of the most intriguing findings concerns adherence itself. Only 44.5 percent of dupilumab initiators met the six-month adherence definition, compared with 59.1 percent of mepolizumab initiators. The dosing schedules may partly explain the gap: dupilumab is injected every two weeks, while mepolizumab is administered every four weeks and can be given in a physician’s office—75.3 percent of mepolizumab patients received office administration versus 18.6 percent of dupilumab patients. Prior research has shown that only about 20 to 60 percent of asthma patients remain adherent to biologics after one year, with adherence dropping further among Medicare beneficiaries, who often face logistical hurdles in managing frequent self-injections. For older adults juggling multiple chronic conditions, a monthly office visit may simply be easier to sustain than a fortnightly home injection routine.

The study’s strengths are considerable: a large, contemporary claims dataset; a clinically complex population underrepresented in prior comparative analyses; rigorous overlap weighting that balanced severity markers; and a pre-specified non-inferiority framework. But the authors are candid about limitations. Administrative claims cannot capture lung function, eosinophil counts, fractional exhaled nitric oxide, immunoglobulin E levels, smoking status, or symptom burden, leaving room for residual confounding. The while-on-treatment design is vulnerable to informative censoring when patients discontinue or switch therapy, and because the adherent subgroup was defined by post-index behavior, its findings should be read as associations among adherent patients rather than causal effects of adherence itself. The observation window also overlapped the COVID-19 pandemic, though both cohorts experienced the same temporal disruptions. Results from Medicare fee-for-service beneficiaries may not generalize to the broader US asthma population.

Even with those caveats, the findings land at a moment when biologic selection in asthma has become one of the most consequential—and expensive—decisions in respiratory medicine. By demonstrating that mepolizumab matches dupilumab on hospitalizations, outperforms it on exacerbations in the full cohort, and achieves superior hospitalization outcomes among patients who stick with therapy, the study gives clinicians and payers a data-driven foundation for choosing between two mechanistically distinct antibodies. It also underscores a broader lesson for the biologic era: in real-world populations of older, multimorbid patients, dosing frequency, administration setting, and adherence may shape outcomes as powerfully as molecular target does. Future research, the authors suggest, should probe which patient subgroups benefit most from each agent, moving the field closer to truly personalized biologic selection for severe asthma.

Subject of Research: Real-world comparative effectiveness of the biologics mepolizumab and dupilumab for asthma outcomes in Medicare beneficiaries

Article Title: Comparative Effectiveness of Mepolizumab Versus Dupilumab in Medicare Fee-for-Service Beneficiaries with Asthma: A Real-World Cohort Study

Article References: Germain, G., Burrows, E., Klimek, J., Gravelle, P., Laliberté, F., & Deb, A. (2026). Comparative Effectiveness of Mepolizumab Versus Dupilumab in Medicare Fee-for-Service Beneficiaries with Asthma: A Real-World Cohort Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03825-8

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03825-8

Keywords: asthma, mepolizumab, dupilumab, biologics, Medicare, real-world evidence, comparative effectiveness, asthma exacerbations, asthma hospitalizations, type 2 inflammation, interleukin-5, IL-4 receptor