The Impact of BMI on the Effect of Biologic Agents for Severe Asthma

Abstract

Introduction

The association between severe asthma and obesity is well established, as higher body mass index (BMI) is associated with higher prevalence and incidence of severe asthma. Biologic agents have been recently developed for severe asthma treatment. However, the efficacy of biologic agents in patients with higher BMI is not well studied. The aim of this systematic review was to determine whether there is an association between BMI and the response to five novel biologic agents.

Methods

Our study design followed the PRISMA guidelines. A literature search was performed using the PubMed/Medline and the Scopus databases up to May 2025 for the following agents: mepolizumab, benralizumab, dupilumab, reslizumab, and tezepelumab. After meticulous screening, 21 articles were selected.

Results

Studies on mepolizumab showed that higher BMI was associated with failure to achieve clinical remission, while BMI < 30 kg/m² was associated with better clinical outcomes. Regarding benralizumab, significant improvements were observed in respiratory symptoms and reductions in annual asthma exacerbation rate for patients with BMI ≤ 35 kg/m² but not for patients with BMI > 35 kg/m². One study about dupilumab describes it as equally effective across all BMI levels. Reslizumab appears to be effective across different BMI levels; however, effectiveness seems to decrease in patients with high BMI. Regarding tezepelumab, no study was found.

Conclusions

Biologic agents are effective treatments for severe asthma, although mepolizumab, benralizumab, and reslizumab appear to have better results in patients with lower BMI. Dupilumab appears to be equally effective across all BMI categories, while no data are available for tezepelumab. More studies in patient populations with severe asthma and comorbid obesity are needed to evaluate the effectiveness of biologic therapies in this specific category of patients.

Trial registration

Registration and protocol: PROSPERO CRD42024609708.

Plain Language Summary

Individuals with obesity are more likely to have severe asthma, as higher body weight is often linked to worse asthma symptoms. Biologic agents have recently been developed to target specific inflammatory pathways that are activated in patients with severe asthma. However, it remains unclear whether these medications are equally effective in patients with and without obesity. In this study, we aimed to examine the association between body mass index (BMI) and the response to five of the most commonly prescribed biologic agents (mepolizumab, benralizumab, dupilumab, reslizumab, and tezepelumab). Our findings suggest that BMI may influence the effectiveness of some biologic agents, as mepolizumab, benralizumab, and reslizumab appear to work better in patients with lower BMI. Yet, dupilumab appears to be equally effective in all patients, regardless of their BMI. No studies on tezepelumab in patients with asthma and comorbid obesity met our inclusion criteria. Future research is needed to identify the most effective medications across different BMI categories.

Key Summary Points

Benralizumab significantly improved respiratory symptoms and reduced the annualized exacerbation rate (AER) in patients with a body mass index (BMI) ≤ 35 kg/m², but it was less effective in those with a BMI > 35 kg/m².

In patients treated with mepolizumab, BMI< 30 kg/m² was associated with better clinical outcomes and remission, whereas a high BMI was associated with worse clinical outcomes, with diminished efficacy observed in obese patients.

Dupilumab appears equally effective across all BMI levels.

Reslizumab appears to be effective across different BMI levels, however effectiveness seems to decrease in patients with a high BMI.

Further research is necessary to evaluate the effects of tezepelumab in patients with asthma and comorbid obesity.

Introduction

Asthma is a major disease that affects more than 300 million people worldwide [1]. Severe asthma is defined by the World Health Organization (WHO) as the type of asthma that: (i) is uncontrolled, as yet untreated, (ii) is uncontrolled due to adherence problems, persistent triggers, or comorbidities, (iii) is uncontrolled despite maximum therapy or is controlled that can only be maintained with maximum therapy and affects approximately 5–10% of asthma population [2]. According to the Global Initiative for Asthma (GINA) guidelines, “severe” asthma is a subset of difficult-to-treat asthma. It is uncontrolled despite good adherence to maximal optimized inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA), treatment and management of contributory factors, or that worsens when high-dose treatment is decreased [3].

Severe asthma is usually treated with a combination of drugs, including high-dose ICS, beta-2 agonists, systemic corticosteroids, and a variety of biologic agents [4], and its association with obesity and higher body mass index (BMI) is well established, since higher BMI is associated with a higher prevalence and incidence of both asthma and severe asthma [5, 6]. Asthma in obesity is considered a low-T2-related progress, characterized by increased neutrophilic inflammation and innate immune activation, while serum Interleukin-6 (IL-6) levels are increased [7]. Other studies, however, report an eosinophilic inflammation component in obese asthmatic patients. Desai et al. reported that sputum Interleukin 5 (IL-5) levels were increased in patients with obesity compared to overweight and lean patients and significantly correlated to BMI [7]. Sputum or blood eosinophils did not correlate with BMI. Examining bronchoscopy specimens of these patients, the authors found that biopsies of obese patients had significantly higher submucosal eosinophils compared to the ones of lean patients [8].

Many biologic agents have been used in the treatment of severe asthma, such as omalizumab, mepolizumab, benralizumab, dupilumab, reslizumab, and tezepelumab. Omalizumab is a monoclonal anti-IgE antibody [9]. Benralizumab is a monoclonal anti-Interleukin 5 receptor (anti-IL-5R) antibody [10] that binds the receptor of IL-5 and inactivates it. Mepolizumab and reslizumab are also antibodies that block IL-5 signaling [11, 12]. Dupilumab is a monoclonal antibody that inactivates the Interleukin-4 receptor (IL-4R) [13], and tezepelumab is a monoclonal anti-thymic stromal lymphopoietin (TSLP) antibody that binds TSLP and blocks TSLP binding to its receptor [14]. The roles of both Interleukin-4 (IL-4) and IL-5 are crucial in the development of asthma, as they mediate a T-helper-2 (Th2) response and promote eosinophil differentiation, transmigration, survival, and degranulation, as well as mucus secretion [15, 16] and thus blocking their action can provide significant relief in asthmatic patients. Moreover, the role of TSLP as a cytokine is to participate in allergic inflammatory responses by acting on innate immune cells [14].

Recent studies are investigating whether there is an association between the response to biologic agents and BMI. More specifically, some of them indicated that higher BMI is associated with poorer response to omalizumab [17, 18], while others reported no differences in response across all BMI levels [19, 20]. The purpose of this review is to determine whether there is an association between BMI and the response to five other biologic agents—mepolizumab, benralizumab, dupilumab, reslizumab, and tezepelumab, in order to enlighten our knowledge on which are the appropriate drugs to use across each BMI category.

Methods

Search Strategy

Our study design follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines described in 2020 (PROSPERO registration number CRD42024609708) [21]. A literature search was conducted using the PubMed/Medline and the Scopus databases for the terms “drug + BMI”, “drug + bodyweight”, “drug + obesity” for each of the five drugs, respectively (mepolizumab, benralizumab, dupilumab, reslizumab, tezepelumab), which retrieved a total of 309 total articles for all five drugs, while seven additional articles where manually added. The authors screened all articles published until May 2025 for potential suitability. After removing all the duplicates, the authors screened the remaining abstracts and excluded articles unrelated to the topic. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Eligibility Criteria

Inclusion criteria for this systematic review were: (i) observational studies (prospective and retrospective cohort studies) that tested the efficacy of the selected biologic agents across different BMI levels, (ii) observational studies that tested the efficacy of biologic agents in obese and non-obese patients, (iii) studies that tested these drugs only in obese patients, and (iv) studies that tested our selected biologic agents in patients with a mean BMI that was higher than normal.

Exclusion criteria were: (i) reviews, (ii) meta-analyses, (iii) conference abstracts, (iv) letters to editors, (v) case reports, (vi) case series, (vii) non-English publications, and (viii) publications where we could not retrieve the full text. Articles relevant to the topic were further analyzed. Overall, 20 articles were finally used for the analysis of this review. A summary of our selection process can be found in Fig. 1.

Fig. 1.

Literature review flowchart

Data Analysis

Due to the different types of studies that were retrieved and their heterogeneity, we decided to not perform any statistical analysis or meta-analysis. Our findings are only described narratively.

Results

Overall, 21 studies fulfilled our inclusion and exclusion criteria and were further assessed. More specifically, 13 studies were about mepolizumab, eight about benralizumab, one about dupilumab, two about reslizumab, and zero about tezepelumab. Some studies involved more than one drug and are discussed separately in each session.

Mepolizumab

Vetchá et al. [22] studied the effect of different dosage forms of mepolizumab in severe asthma. They reported that there was a statistically significant decrease in blood eosinophil count (BEC), asthma exacerbation rate (AER), OCS, and a statistically significant increase in forced expiratory volume in 1 s (FEV₁) and the Asthma Control Test (ACT) in all BMI groups (< 25, 25–30, > 30) at 3 months (vs. baseline). Additionally, there was a statistically significant decrease in BEC for BMI below 25 or above 30 and in OCS for BMI less than 30 after 6–9 months of treatment. However, they noted that these findings, although statistically significant, were minimal and most likely clinically insignificant. Therefore, they claimed that BMI did not significantly influence treatment outcomes in the patients studied.

Papaioannou et al. [23] reported in a post hoc analysis of a prospective real-life study of patients treated with mepolizumab for 2 years that remission was achieved in 27.4% and 22% after 12 and 24 months, respectively. Remitters had better asthma control and needed lower doses or no maintenance OCS at baseline, whereas GERD seemed to be an important factor that affects remission and relapse. BMI did not play a significant role in either outcome.

Carpagnano et al. [24], in their study regarding the characteristics of patients with severe asthma who might achieve clinical remission with mepolizumab or benralizumab, found that clinical remission was more likely in patients with lower BMI and less likely in those with higher BMI (mean BMI of patients with non-clinical remission = 27.7). Patients less likely to achieve a clinical remission under mepolizumab were those with higher BMI, lower levels of FeNO, and a higher number of exacerbations the year prior to study enrollment.

Thomas et al. [25] performed an observational study where they treated patients with severe asthma with biologic agents (omalizumab or mepolizumab). Also, they determined factors that could affect the response to the treatment. More precisely, a lower BMI was associated with better response to the drug (baseline BMI: 29.71) and obesity was associated with no clinical remission. The odds of achieving clinical remission were reduced by 9% for each unit increase in BMI.

Valverde-Monge et al. [18] tried to establish predictors of failure to respond to mepolizumab in 112 patients with severe asthma. They found that in patients treated with mepolizumab (baseline mean BMI = 27.4), there was an increase in FEV1 of 0.27 ± 0.50 l, a statistically significant improvement in ACT and MCID > 3 points with this drug (7 ± 1.78). In addition, there was a significant reduction in the total dose of mOCS in all treatment groups. The study also showed that higher BMI predicted statistically significant failure to respond to all biologic therapies in this study (omalizumab, mepolizumab, reslizumab, benralizumab). The relative risk was 14% (95% CI: 1.06–1.23; p < 0.001) [18]. There was no statistically significant difference between non-responders and super-responders regarding pre-treatment FENO, IgE, or eosinophil levels.

Özden et al. [26] measured the response to mepolizumab and omalizumab in obese and non-obese patients (patients with BMI > 30 were classified as obese). Regarding mepolizumab, there was no difference in the improvement in ACT scores and the reduced number of asthma attacks between obese and non-obese groups. However, FEV1 had a greater increase in non-obese patients treated with mepolizumab. Non-obese patients with a smoking history of more than 10 pack-years had significantly higher blood eosinophils compared to non-obese patients. Response to treatment was independent of the number of eosinophils both in obese and non-obese patients.

Crimi et al. [27] measured the effectiveness of mepolizumab in patients with other comorbidities while also determining whether other characteristics affected the response. Regarding BMI, higher BMIs (> 25) did not affect the response to the drug. No established predictive outcomes based on BMI were found. Regarding the blood eosinophil count, there was no difference between obese and non-obese patients, either at baseline or after treatment.

Kavanagh et al. [28] measured the characteristics of severe asthmatics who responded well to mepolizumab and reported that a lower BMI is a predictor of a better outcome. Also, they found that higher BMI is associated with lesser response: responders had a BMI of 29.01 ± 5.09 vs. 32.21 ± 7 in non-responders, p = 0.014. This difference did not remain significant after regression analysis. Biomarkers such as blood eosinophils, IgE, the presence of atopy, and FENO were not significantly associated with remission.

Harvey et al. [29] also tried to establish the characteristics of patients who consistently respond better to mepolizumab. More specifically, they reported that a higher BMI (≥ 30) predicted a poorer response in multivariate regression analysis (p = 0.043). This was also true for the super-responders according to the ACQ-5 score [median BMI of super-responders 27.8 (23.8–31.8) vs. 31.0 of the non-super-responders (26.4–35.7) kg/m²; p = 0.006]. Super-responders were predominantly females, had shorter asthma duration, higher eosinophils, and were less frequently smokers. Moreover, patients who achieved control were more likely to have a lower baseline BMI (median 27.5 (23.8–30.5) vs. 31.8 (27.1–36.6) kg/m²; p < 0.001). The authors noted that patients with a baseline BMI < 35 had a statistically significant difference in their ACQ-5 scores compared to those with BMI > 35 at 6 months of follow-up. However, there was no statistically significant difference between the two groups at the 12-month follow-up. Also, there was no statistically significant difference in FEV1% predicted (pre-BD) and AQLQ(S) mean scores in patients with baseline BMI < 35 and BMI ≥ 35 at both 6 months and 12 months.

Drick et al. [30] studied anti-IL-5 therapy in patients with severe asthma and measured whether the response to it could be predicted based on certain baseline characteristics. Regarding BMI, however, it did not predict treatment response. The median BMI was 28 kg/m² among responders, compared to 31 kg/m² among non-responders (p = 0.078). However, this outcome could be attributed to the small number of non-responders. Baseline IgE or blood eosinophils were not predictors of response.

Ortega et al. [31] (2014), however, in a randomized controlled trial measured a greater reduction in AER in obese patients (BMI = 33.9) compared to non-obese (BMI = 25.3), with obese and non-obese having a 67% and 35% reduction in exacerbations, respectively. The authors divided the patients into four clusters: cluster 1 with low eosinophils and IgE, cluster 2 with low airway reversibility, cluster 3 with non-obese patients with higher levels of reversibility, with a mean value of 28.7% and cluster 4 included obese patients, mostly women with less atopy and with higher airway reversibility (mean value: 28.3%). Also, a total of 43.1% of patients were atopic with a history of exacerbations; their mean predicted post-BD FEV₁ at baseline was 66% and they had more comorbidities, including hypertension, weight gain, and anxiety.

Pavord et al. [32] in their study, which was the largest study ever conducted in patients with severe asthma, found that patients with BMI less than 25 kg/m² or with a BMI greater than or equal to 30 kg/m² have statistically significant reduction in AER when taking mepolizumab. However, for those with a BMI between 25 and 29.9 kg/m², no statistically significant difference was found. Baseline blood eosinophilic count was associated with response.

Finally, the study of Casale et al. [33], although the authors did not measure response to mepolizumab across BMI levels, measured its effectiveness in severe asthmatics with comorbid obesity and reported that mepolizumab reduces AER and improves their quality of life. Table 1 summarizes findings on mepolizumab.

Table 1.

Summary of findings on mepolizumab

Author/year	Type of study	Number of participants	Endpoint	BMI cut-off	Primary outcome	Exacerbations (median, IQR)	FEV1 (median (SD) l)	Secondary outcomes
Vetchá et al. 2025 [22]	Retrospective study	66	BEC, ER, ACT, FEV1, mOCS	BMI < 25 kg/m2, BMI = 25–30 kg/m2 BMI > 30 kg/m2	No clinically significant effect of BMI in response to mepolizumab	(%) At 3 months vs. baseline: BMI < 25: 100.0 (80.0–100.0) BMI = 25–30: 83.3 (50.0–100.0) BMI > 30: 1 00.0 (85.0–100.0) At 6–9 months vs. baseline: BMI < 25: 100.0 (90.0–100.0) BMI = 25–30: 100.0 (50.0–100.0) BMI > 30: 100.0 (75.0–100.0)	(%) At 3 months vs. baseline: BMI < 25: 12.3 (− 2.1–26.0) BMI = 25–30: 10.7 (0.0–44.8) BMI > 30: 12.7 (− 2.3–21.5) At 6–9 months vs. baseline: BMI < 25: 13.3 (0.0–26.0) BMI = 25–30: 21.9 (− 0.1–41.4) BMI > 30: 10.1 (− 8.4–20.5)	-
Papaioannou et al. 2025 [23]	Prospective, multicenter observational study	146	No exacerbations, no mOCS use treatment, ACT ≥ 20, stable or improved lung function	BMI of patients with sustained remission at 24 months: 27.9 [25.1–29.0] vs. 27 [24.6–31] of patients with remission	Remission in 27.4% and 22% of treated patients after 12 and 24 months, respectively	From 4.3 ± 1.9 to 1.2 ± 1.8 after 12 months	–	No difference in BMI between remitters and non-remitters
Carpagnano et al. 2024 [24]	Retrospective observational study	266 (154 were treated with mepolizumab and 112 with benralizumab)	No exacerbations, no mOCS use treatment, ACT ≥ 20 and FEV1 ≥ 80%	BMI of patients with non-clinical remission: 27.7 [23.8–30.8]	Better response in lower BMI/ higher BMI as a predictor of non-clinical remission	0 [0–1] (in non-clinical remission patients)	2 ± 0.78 (in non-clinical remission patients)	Patients with lower baseline BMI had better FEV1 and less exacerbations
Thomas et al. 2024 [25]	Observational study	453 (278 were treated with mepolizumab and 175 with omalizumab)	No exacerbations, no mOCS use, ACQ-5 ≤ 1, optimization of lung function	Baseline BMI: 29.71 [25.77, 34.58]	Better response in lower BMI	–	–	BMI: OR = 0.91, CI [0.85–0.96] Obesity: OR = 0.41 CI [0.21–0.80]
Valverde-Monge et al. 2024 [18]	Comparative study	429 (209 were treated with omalizumab, 112 with mepolizumab, 19 with reslizumab, and 89 with benralizumab)	No exacerbations, ACT > 20, no SCS, pre-BD FEV1 > 80% predicted	Baseline BMI, mean (SD): 27.4 (5.2)	Higher BMI as a predictor of non-response	Exacerbations/year, median (SD) 0.5 (0.8)	2.1 (0.8) (after mepolizumab treatment)	n (%): R: 56 (50), non-R: 11 (9.8), super-R: 45 (40.2), clinical remission: 22 (19.6) RR = 14% (95% CI:1.06–1.23; p < 0.001)
Özden et al. 2023 [26]	Retrospective, cross-sectional study	121 (88 were treated with omalizumab and 33 with mepolizumab)	ACT, numbers of asthma attacks, FEV1, FEF25/75, and changes in TEC	Obese: BMI ≥ 30 kg/m2 non-obese: BMI < 30 kg/m2	Better response in lower BMI	–	0.280 and 0.510 increase in obese and non-obese, respectively	Non-obese patients had a greater increase in FEV1
Crimi et al. 2020 [27]	Retrospective cohort study	31	BEC, ACT score, FEV1 values, and OCS	BMI ≥ 25 kg/m2 comorbidity: obesity	No predictive outcomes based on BMI	Exacerbations/year are − 6 (− 12– − 4) and − 7 (− 12 to  − 3) in non-obese and obese, respectively	FEV1 is 0.142 l and 0.09 l in non-obese and obese, respectively	Higher BMI did not affect drug response in patients with other comorbidities
Kavanagh et al. 2020 [28]	Retrospective observational cohort study	99	No mOCS, no exacerbations	BMI of patients with non-clinical remission: 32.31 ± 7.0	Lower BMI was associated with responder and super-responder status	–	–	Higher BMI was associated with lesser response but did not remain significant after regression analysis
Harvey et al. 2020 [29]	Prospective observational study	309	Symptom control, quality of life, and lung function	BMI < 30 kg/m2 BMI ≥ 30 kg/m2	BMI ≥ 30 predicted a lesser response	Annual exacerbations resulting in OCS treatment: 1.41, hospitalizations 0.26, emergency room visit 0.17 and unscheduled doctor visits 0.23	FEV1% predicted in 12-month follow-up: for BMI < 35:66.6 (– 1.11, 15.79) for BMI > 35: 3.42 (– 1.08, 9.25)	Patients with a baseline BMI < 35 had a statistically difference in their ACQ-5 scores compared to those with BMI ≥ 35 at 6 months (– 2.11 ± 1.16 vs. – 1.74 ± 1.21, p = 0.039). However, there was no statistically significant difference in ACQ-5 scores between the two groups at the 12-month follow-up (– 2.21 ± 1.17 vs. – 2.21 ± 1.32, p = 0.98). Also, there was no statistically significant difference in FEV1% predicted (pre-BD) and AQLQ(S) mean scores in patients with baseline BMI < 35 and BMI ≥ 35 at 6 months and 12 months
Drick et al. 2018 [30]	Single-center retrospective study	42	Improvement of lung function, decrease of eosinophils, and improvement of subjective condition	BMI of non-responders: 31 [27–36]	No predictive outcomes based on BMI	No prediction about the non-responder group could be made due to the small number of non-responders	A median increase of 0.600 in the responder group and a decrease of 0.100 in the non-responder group	None of the non-responders showed improvement of lung function
Ortega et al. [31] 2014	Randomized controlled trial	616	AER	BMI < 30 BMI ≥ 30	Better response in obese with more comorbidities and airway reversibility	Non-obese and obese had a 35% and 67% reduction in exacerbations, respectively	Low FEV1 (66% predicted)	Higher reduction in AER in obese patients
Pavord et al. [32] 2012	Randomized controlled trial	621	AER, FEV1, ACQ and AQLQ scores, blood and sputum eosinophil counts	BMI < 25, 25 ≤ BMI < 30, BMI ≥ 30	Better response in higher or lower BMI, not in intermediate	2.40 (0.11) in placebo group, 1.24 0.12) 75-mg group, 1.46 (0.11) in 250-mg group, 1.15 (0.12) in 750-mg group	Change in pre-BD FEV1 from baseline: 0.6 in the placebo group, 0.121 in the 75-mg group, 0.140 in the 250-mg group and 0.115 in the 750-mg group	Reduced AER with higher or lower BMI, but not with intermediate BMI
Casale et al. [33] 2021	Retrospective observational cohort study	639	AER and exacerbation-related health care resource utilization	Response in obese patients	–	Significant reduction of 52% in the mean AER	–	Reduced AER, improved quality of life, asthma control independent of obesity

ACT Asthma Control Test, ACQ Asthma Control Questionnaire, AER asthma exacerbation rate, AQLQ Asthma Quality of Life Questionnaire, BEC blood eosinophil count, BMI body mass index, ER exacerbation rate, FEF25/75 forced expiratory flow between 25 and 75% of forced vital capacity, FEV1 forced expiratory volume in 1 s, mOCS maintenance oral corticosteroids, RR relative risk, SCS systemic corticosteroids, SD standard deviation

Benralizumab

Jackson et al. [34] reported a statistically significant negative association between higher BMI, maintenance oral corticosteroids (mOCS), dose, and clinical remission at 1 year. They also found that patients with a BMI < 30 were 2.5 times more likely to achieve remission compared to those with BMI ≥ 30, at 2 years. Moreover, 42% of patients with a BMI < 30 and 23% with a BMI ≥ 30 achieved remission at 2 years. The study showed that each 1-unit increase in BMI decreased the likelihood of remission by about 7%.

Al-Ahmad et al. [35] found that each 1-unit increase in BMI doubled the likelihood of a poor response to benralizumab. Their hypothesis is that the modest response in obese patients may be due to dose-related insufficiency or the development of non-type 2 inflammation. They also reported that a reduced treatment efficacy in high-BMI patients may also result from systemic inflammation caused by obesity-related cytokines like (tumor necrosis factor-α) TNF-α, Interleukin-6 (IL-6), and leptin.

Valverde-Monge et al. [18] tried to establish predictors of failure to respond to benralizumab in 89 patients with severe asthma. They found that in patients treated with benralizumab (baseline mean BMI = 26.8 kg/m²), there was an increase in FEV1 of 0.23 ± 0.49 l, and statistically significant improvements in ACT and MCID > 3 points with this drug (6.45 ± 1.78). In addition, there was a significant reduction in the total dose of OCS, with a greater reduction in patients treated with reslizumab or omalizumab than benralizumab. Finally, the study showed that higher BMI predicted statistically significant failure to respond to all biologic therapies in this study (omalizumab, mepolizumab, reslizumab, benralizumab).

Sposato et al. [17] suggested that benralizumab’s ability to clear eosinophils may aid asthma remission more effectively, especially in patients with rhinitis and low BMI, which could indicate a higher likelihood of complete asthma disappearance (BMI of patients with non-clinical remission: 27 ± 4.1). However, there was no statistically significant differences in BMI between asthma responders and non-responders (p = 0.059) nor obesity (p = 0.430).

Yamada et al. [36] reported the results of 64 patients with severe asthma treated with benralizumab. Five clusters of clinical response were found. Eight patients with higher BMI had no FEV1 improvement after treatment and were characterized by low T2-inflammation markers.

Panettieri et al. [37] observed that patients with BMI ≤ 35 kg/m² have a statistically significant improvement in Asthma Control Questionnaire 6 (ACQ-6) [38] and St. George’s Respiratory Questionnaire (SGRQ) [39] scores, which demonstrated a consistent treatment effect favoring benralizumab over placebo. Nevertheless, patients with BMI > 35 kg/m² did not have a statistically significant improvement in ACQ-6 and SGRQ scores.

FitzGerald et al.’s [40] CALIMA study involved 1306 patients with severe asthma, which were randomly assigned (1:1:1) to receive a 56-week treatment with either benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg once every 4 weeks for the first three doses and then once every 8 weeks (Q8W), or placebo. A total of 728 patients were included in the primary analysis population. Benralizumab significantly reduced the annual AER, the pre-bronchodilator FEV1 and total asthma score compared to placebo. The authors reported no statistically significant reduction in the annual AER at 56 weeks for patients with a BMI > 35 kg/m² that took benralizumab Q4W or Q8W compared to those who took the placebo. In addition, they reported that for patients who were taking benralizumab Q4W or Q8W and had BMI ≤ 35 kg/m², a statistically significant reduction in the annual AER ratio was found.

Bleecker et al.’s [41] SIROCCO study involved 1205 patients with severe asthma, which were randomly assigned (1:1:1) to benralizumab 30 mg either Q4W or Q8W or placebo Q4W for 48 weeks as an add on to their standard treatment. The results reported were similar to the CALIMA study regarding annual AER, pre-bronchodilator FEV1, and total asthma score compared to placebo. No significant reduction in AER was found for BMI > 35 kg/m², however a significant reduction was evident for BMI ≤ 35 kg/m². Table 2 summarizes the findings regarding response to benralizumab across BMI levels.

Table 2.

Summary of findings on benralizumab

Author/year	Type of study	Number of participants	Endpoint	BMI cut-off	Primary outcome	Exacerbations	FEV1	Secondary outcomes
Jackson et al. [34] 2024	Multicenter study	276	No exacerbations, cessation of mOCS, ACQ6 < 1.5	BMI: < 30/ ≥ 30	Increasing BMI as a predictor of no clinical remission	Mean AER at 1 year and 2 years: 1.0 (0.7–1.2) and 0.9 (0.6–1.1), respectively, for BMI < 30, 1.3 (1.0–1.6) and 1.3 (1.0–1.6) respectively BMI ≥ 30/44% and 50% of patients with a BMI ≥ 30 and BMI < 30, respectively, had 0 exacerbation in week 48 and 39% and 68% in week 100	Missing data on lung function due to COVID-19 pandemic	An increase of one unit of BMI decreasing the odds of meeting clinical remission by approximately 7%
Al-Ahmad et al. [35] 2023	Retrospective single-center cohort study	162 (133 were treated with omalizumab, 29 with benralizumab)	asthma exacerbations, OCS, ACT score, post-BD FEV1%	Overweight	Poor response in higher BMI	–	–	Each 1-unit increase in BMI doubles the likelihood of a poor response
Valverde-Monge et al. [18] 2024	Comparative study	429 (209 (48.7%) omalizumab, 112 (26.1%) mepolizumab, 19 (4.4%) reslizumab and 89 (20.7%) benralizumab)	No exacerbations, ACT > 20, no SCS, pre-BD FEV1 > 80% predicted	Baseline BMI, mean (SD): 28.6 (7.3)	Higher BMI as a predictor of non-response	Exacerbations/per year median, (SD) 0.3 (0.8)	2.2 (0.7) after benralizumab treatment	n (%): R: 34 (38.2), non-R: 7 (7.9), super-R: 48 (53.9), clinical remission: 23 (25.8)
Sposato et al. [17] 2023	Retrospective observational cohort study	Omalizumab, mepolizumab, benralizumab, and dupilumab (302, 55, 95, and 34 patients, respectively)	ACT ≥ 20, zero exacerbations, no use of OCS, and a FEV1% ≥ 80%	BMI of patients with non-clinical remission: 27 ± 4.1	Better response in low BMI/poor response in higher BMI	–	–	Rhinitis and low BMI may be traits that could identify subjects more prone to asthma remission
Yamada et al. [36] 2021	Retrospective observational cohort study	64	ACT, FEV1, %FEV1, FeNO, BEC, serum IgE, and OCS doses	BMI of patients with non-clinical remission: 26.4	Better response in low BMI but not statistically significant	–	Change in FEV1 from baseline: – 110 ml in patients with high BMI, significantly less than in other groups	Higher BMI associated with less atopy and eosinophilic inflammation
Panettieri et al. [37] 2020	Randomized controlled trial	233	pre-BD FEV1, ACQ 6, SGRQ	Morbidly obese: BMI > 35 kg/m2	Poor response in morbidly obese	–	Change in pre-BD FEV1 from baseline: 0.227 in benralizumab group and 0.148 in placebo group at day 84	Significant improvements in respiratory symptoms with BMI ≤ 35 kg/m2
FitzGerald et al. [40] 2016	Randomized, double-blind, placebo-controlled phase 3 trial	1306	Annual AER, pre-BD FEV1, total asthma symptom score	BMI ≤ 35 kg/m2 BMI > 35 kg/m2	Better response in lower BMI	Annual AER: 0.60 (0.48–0.74) in benralizumab 30-mg Q4W group, 0.66 (0.54–0.82 in benralizumab 30-mg Q8W group and 0.93 (0.77–1.12) in the placebo group	Change of pre-BD FEV1: 0.340 in benralizumab 30-mg Q4W group, 0.330 in benralizumab 30-mg Q8W group and 0.215 in the placebo group	No significant reduction in AER for BMI > 35 kg/m2, significant reduction for BMI ≤ 35 kg/m2
Bleecker et al. [41] 2016	Randomized, multicenter, placebo-controlled phase 3 trial	1205	AER, pre-BD FEV1, total asthma symptom score	BMI (≤ 35/ > 35 kg/m2)	Better response in lower BMI	Annual AER in patients receiving high-dosage ICS with baseline BEC ≥ 300 cells/μl: 0·73 (0.60–0.89) in benralizumab 30-mg Q4W group, 0.65 (0.53–0.80) in benralizumab 30-mg Q8W group and 1.33 (1.12–1.58) in the placebo group	Change of pre-BD FEV1 in patients receiving high-dosage ICS with baseline BEC ≥ 300 cells/μl: 0.73 (0.60–0.89) in benralizumab 30-mg Q4W group, 0.65 (0.53–0.80) in the benralizumab 30-mg Q8W group and 1.33 (1.12–1.58) in the placebo group	No significant reduction in AER for BMI > 35 kg/m2, significant reduction for BMI ≤ 35 kg/m2

ACQ6 Asthma Control Questionnaire 6, ACT Asthma Control Test, BEC blood eosinophil count, BMI body mass index, ICS inhaled corticosteroids, mOCS maintenance oral corticosteroids, OCS oral corticosteroids, BD bronchodilator, Q4W once every 4 weeks, Q8W once every 8 weeks (first three doses Q4W), SCS systemic corticosteroids, SGRQ St. George’s Respiratory Questionnaire, TEC total peripheral eosinophil count

Dupilumab

Regarding dupilumab in severe asthma and BMI, only one related study was found. In the study of Sposato et al. [17] (2023), authors treated patients with severe asthma with omalizumab, mepolizumab, benralizumab, and dupilumab, and reported the characteristics of those successfully treated with each drug. Regarding dupilumab and BMI, no difference was found in the response to the drug across all BMI levels. Table 3 summarizes findings on dupilumab.

Table 3.

Summary of findings on dupilumab

Author/year	Type of study	Number of participants	Endpoint	BMI cut-off	Primary outcome	Exacerbations	FEV1	Secondary outcomes
Sposato et al. [17] 2024	Retrospective observational cohort study	486 (302 were treated with omalizumab, 55 with mepolizumab, 95 with benralizumab, and 34 dupilumab	ACT ≥ 20, zero exacerbations, no use of OCS, FEV1 ≥ 80%	BMI of patients with non-clinical remission: 27.5 ± 3.7	No response difference across BMI levels	–	–	Seems to be effective in about 25% of cases in inducing asthma disappearance

ACT Asthma Control Test, AER asthma exacerbation rate, BMI body mass index, FEV1 forced expiratory volume in 1 s, OCS oral corticosteroids, SD standard deviation

Reslizumab

Valverde-Monge et al. [18] tried to establish predictors of failure to respond to reslizumab in 19 patients with severe asthma. They found that in patients treated with reslizumab (baseline mean BMI = 26.8), there was an increase in FEV1 of 0.39 ± 1.44L and statistically significant improvements in ACT and MCID > 3 points with this drug (10.26 ± 2.22). In addition, there was a significant reduction in the total dose of mOCS, with a greater reduction in patients treated with reslizumab than benralizumab. Finally, the study showed that higher BMI predicted statistically significant failure to respond to all biologic therapies in this study (omalizumab, mepolizumab, reslizumab, benralizumab).

Bernstein et al. [42] investigated the effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma. They found no significant difference in the AER for reslizumab in patients with BMI < 30 kg/m² or BMI ≥ 30 kg/m². Mean BMI did not differ between high and low baseline eosinophils. They also noted that higher trough serum reslizumab concentration was observed in patients with a lower bodyweight (mean BMI = 28.3 kg/m²). Furthermore, higher trough concentration values were associated with a lower annual frequency of clinical asthma exacerbations. Specifically, achieving maximum efficacy requires a higher dose than 110-mg subcutaneous reslizumab. Table 4 summarizes the findings on reslizumab.

Table 4.

Summary of findings on reslizumab

Author/year	Type of study	Number of participants	Endpoint	BMI cut-off	Primary outcome	Exacerbations	FEV1	Secondary outcomes
Valverde-Monge et al. 2024 [18]	Comparative study	429 (209 were treated with omalizumab, 112 with mepolizumab, 19 with reslizumab, and 89 with benralizumab)	No exacerbations, ACT > 20, no SCS, pre-BD FEV1 > 80% predicted	Baseline BMI, mean (SD): 26.8 (5.4)	Higher BMI as a predictor of non-response	Exacerbations/year, median (SD) 0.7 (2.1)	2.35 (0.7) after dupilumab treatment total	n (%): R: 6 (31.6), non-R:0, super-R: 13 (68.4) clinical remission: 5 (26.3)
Bernstein et al. 2020 [42]	Phase 3, randomized, double-blind, placebo-controlled trial	468 (232 patients were treated with placebo and 236 with subcutaneous reslizumab)	AER, pre-BD FEV1, ACQ-6, AQLQ scores, safety, BEC	BMI < 30 kg/m2 BMI ≥ 30 kg/m2	Maximum efficacy requires higher dose than 110 mg subcutaneous reslizumab	0.75 when eosinophil count 300 to < 400 cells/μl and 0.56 when eosinophil count ≥ 400 cells/μl	–	Higher trough serum reslizumab concentration in patients with a lower bodyweight

ACQ-6 Asthma Control Questionnaire 6, ACT Asthma Control Test, AER asthma exacerbation rate, AQLQ Asthma Quality of Life Questionnaire, BD bronchodilator, BEC blood eosinophil count, BMI body mass index, FEF25/75 forced expiratory flow between 25 and 75% of forced vital capacity, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, IL-5 Interleukin-5, OCS oral corticosteroids, R remission, SCS systemic corticosteroids, SD standard deviation

Tezepelumab

After meticulous screening, no related articles were found. The effect of the different biologic agents in severe asthma according to their BMI is summarized in Tables 5 and 6.

Table 5.

Summary of findings on mepolizumab, benralizumab, dupilumab, reslizumab, and tezepelumab in non-obese with severe asthma

Table 6.

Summary of findings on mepolizumab, benralizumab, dupilumab, reslizumab, and tezepelumab in obese with severe asthma

Discussion

The relationship between severe asthma and obesity is well established, as obese patients experience severe asthma more frequently and have a greater risk of hospitalization compared to non-obese asthmatics. Emerging evidence suggests that obesity-associated asthma represents a heterogeneous phenotype with distinct inflammatory, mechanical, and metabolic characteristics that may influence treatment response. Additionally, they have poorer asthma control and lower quality of life. Standard medications, such as ICS and ICS-long-acting beta agonists (LABA), are often less effective in obese asthmatics. The decreased response to medications is likely due to the altered pathogenesis in obesity [43].

The pathophysiology of obesity-related asthma is not well understood, although several explanations have been suggested. Excess fat tissue in the chest and abdomen can cause mechanical forces on the lungs, which can reduce the functional residual capacity (FRC) and the expiratory reserve volume. Also, excess fat can cause airway resistance, airway smooth muscles responsiveness, bronchoconstriction, collapse of small airways, and an increase in lung stiffness. Systemic inflammation in obese asthmatics is characterized by elevated cytokines (TNF-α, IL-6), which also increase airway inflammation. Obesity can also increase submucosal eosinophils, IL-5, and neutrophils, all causing a worsening of the condition. Moreover, higher plasma, airway leptin levels, and reduced airway leptin receptors are associated with asthma severity and airway remodeling, resulting in an increase of airway hyperreactivity (AHR) and serum immunoglobulin E (IgE). Low adiponectin levels cannot inhibit the production of proinflammatory cytokines IL-5 and TNF-a102 and the release of anti-inflammatory cytokines like Interleukin-1 receptor antagonist (IL-1RA) and Interleukin-10 (IL-10). Additionally, oxidative stress worsens symptoms and reduces lung function. Metabolic syndrome in obese-related asthma involves T helper-1 (Th1) polarization, monocyte activation, and dysregulation through insulin resistance and dyslipidemia, which further worsens asthma control. Furthermore, a diet high in fat and low in fiber changes the gut microbiome, which triggers the immune system and leads to airway inflammation. In addition, some comorbidities like gastroesophageal reflux disease (GERD), sleep-disordered breathing (SDB), dyslipidemia, type II diabetes, and hypertension may trigger or worsen asthma. Genetic factors also play a role, as there is an association between specific regions of the human genome, asthma, and obesity. All these factors can act synergistically and contribute to asthma development or worsening in obese [44–47].

Obesity can lead to respiratory symptoms like those seen in non-obese asthmatic patients. This clinical overlap may complicate the assessment of biologic treatment response and underscores the importance of carefully distinguishing asthma-related symptoms from obesity-related respiratory impairment. Failing to recognize these obesity symptoms can pause or alter biologic therapy and potentially lead to worsening control of asthma. This fact emphasizes the importance of addressing comorbidities and ensuring that symptoms similar to asthma are properly considered when evaluating disease progression during treatment [34].

It is important to note that the definitions of response/remission may differ across the aforementioned studies, as may the baseline characteristics of the study populations, which can affect how outcomes are presented. Many phase 2 and 3 studies include BMI cutoffs in their inclusion criteria, potentially excluding data on patients with severe obesity. In these cases, real-world data are important, as they provide information about patients who are often missing from clinical trials.

Obesity-associated asthma can be categorized into two groups: early onset atopic asthma and late-onset nonatopic asthma. Patients in the first group have the most severe disease among obese asthmatics, with Th2 inflammation and their disease does not remit when they lose weight, even though symptoms may improve. They experience more severe airway obstruction and airway hyperresponsiveness compared to non-obese asthmatics with early onset asthma. Airway walls are thick because of the inflammation that expands the airway epithelium and increases mucus secretion. Increased eosinophilic inflammation, glucocorticoid insensitivity, and physical inactivity may help develop this phenotype. In contrast, people in the second group are usually female, with little or no airway inflammation, but significant inflammation in adipose tissue and airway oxidative stress. They have neutrophilic airway inflammation, which resolves when they lose weight, and seems to result from obesity [39]. Also, tidal volume is reduced, as the excess subcutaneous fat in the trunk and the visceral fat are compressing the thorax and the lungs. Patients in this group have a higher morbidity rate and poorer response to ICS [43, 48, 49].

It is noted that the doses of omalizumab and reslizumab are titrated based on body weight. However, for mepolizumab, benralizumab, dupilumab, and tezepelumab, there are fixed doses and they are not titrated based on body weight [50]. This fact raises the question whereas severe asthmatics with high bodyweight are getting proper treatment while taking fixed doses of those biologic agents.

In patients treated with mepolizumab, higher BMI was associated with failure of clinical remission compared to normal BMI [18, 24, 29, 31], while lower BMI was linked to better clinical outcomes and remission [24, 25, 28]. Although mepolizumab led to reductions in the rates of clinically significant exacerbations and improvements in quality of life and asthma control, its efficacy was diminished in obese patients. On the contrary, other studies found that BMI did not predict treatment response [23, 27, 30]. Interestingly, one study reported a higher reduction in AER in obese patients compared to non-obese patients. Some others reported significant AER reductions in patients with a BMI below 25 kg/m² and those with a BMI ≥ 30 kg/m², but not in those with a BMI between 25 and 29.9 kg/m² [37]. In addition, mepolizumab has been shown to reduce AER and improve quality of life in severe asthmatics with comorbid obesity [33]. A meta-analysis of Albers et al. [51] reported adequate response to mepolizumab across all BMI levels and suggested that dose–weight adjustments are not required. Although the odds ratios showed possibly better responses to mepolizumab in those with lower BMIs, statistical/clinical significance could not be established. As has been demonstrated, mepolizumab is effective regardless of BMI and a fixed dose is more suitable than a weight-based dose.

Based on the examined studies, benralizumab can reduce asthma exacerbations in patients with severe uncontrolled eosinophilic asthma and is more efficient in patients with lower BMI [17, 34, 37, 39, 41]. Some other studies reported that higher BMI levels predicted significant failure to respond to the drug [17, 18, 34, 35, 37]. Significant improvements were observed in respiratory symptoms and reductions in annual AER for patients with BMI ≤ 35 kg/m² but not in patients with BMI > 35 kg/m² [37, 40, 41]. The modest response to benralizumab in obese patients could be partially attributed to dosing insufficiency. However, for the time being, given that no real-world studies have examined this possibility, this fact could also be attributed to the systemic inflammation caused by elevated levels of obesity-related cytokines like TNF-α, IL-6, and leptin and to the development of non-type two inflammations, as the drug is targeting type 2 immunity [36].

Regarding dupilumab, there are not enough studies for us to confidently say whether it works better in patients with lower BMIs. The study we found, however, describes that it is equally effective across all BMI levels [17]. On the other hand, dupilumab is also used in the treatment of other conditions, such as atopic dermatitis, and there are studies regarding its effectiveness across BMI levels with controversial results. More specifically, the studies of Nicolosi et al. [52], Ferrucci et al. [53], Gu et al. [54] and Stingeni et al. [55] showed that patients with atopic dermatitis who have BMI < 24–25 respond better to dupilumab therapy, although probably differences were clinically nonsignificant. On the other hand, Tánczosová et al. [56] reported no statistically significant difference between response to dupilumab and BMI.

Reslizumab appears to be effective across different BMI levels [18, 42]. Effectiveness may decrease in patients with high BMI, due to pharmacokinetics and bioavailability of the biologic [57]. Additionally, the reduced effectiveness in patients with asthma with comorbid obesity can be attributed to the weight-based dosing requirement. A study on the efficacy of different doses of reslizumab concluded that a dose of 3 mg/kg or a dose higher than the fixed dose of 110 mg may provide better results than 03 kg/mg, as it significant increases FEV₁, FVC, FEF 25%-75%, and have more improvements in ACQ and AQLQ scores and it is safe [58]. Mukherjee M. et al. reported that weight-adjusted IV reslizumab was superior to fixed-dose SC mepolizumab in attenuating airway eosinophilia in prednisone-dependent patients with asthma, with associated improvement in asthma control. This indirect evidence may reveal that BMI can guide the use of biologics when a weight-adjusted process is available [59].

Apart from these drugs, another biologic agent that could be used in obese patients with asthma is tezepelumab. There are no studies to investigate the effects of tezepelumab in this group of patients. Our literature review yielded one published study that evaluates its efficacy of different doses. The results of this study, which was conducted in patients with a mean BMI = 28.1 ± 5.0, showed that medium and high doses of tezepelumab provide better results than low dose and this fact may be attributed to dose insufficiency [60]. However, it is a promising biologic regarding the obese population because of its impact on type 2 with high Th2 asthma [61]. There have been congress reports investigating the effect of tezepelumab in patients with severe, uncontrolled asthma by baseline BMI. Chupp et al. presented a post hoc analysis of the phase 3, randomized, double-blind, placebo-controlled NAVIGATOR study, which evaluated tezepelumab efficacy across baseline body mass index (BMI) subgroups in patients aged 12–80 years receiving medium- or high-dose inhaled corticosteroids plus additional controller therapy [62]. Patients were randomized to tezepelumab 210 mg or placebo every 4 weeks for 52 weeks, and annualized asthma exacerbation rates (AAERs), including exacerbations requiring hospitalization or emergency department visits, were assessed by BMI (< 25, 25 to < 30, and ≥ 30 kg/m²). Among 1059 treated patients, AAERs increased with higher BMI in placebo-treated patients, while tezepelumab reduced AAERs versus placebo by 54–60% and reduced severe exacerbations by 67–85% across all BMI subgroups. These results demonstrated that tezepelumab significantly reduced asthma exacerbations regardless of baseline BMI, supporting its efficacy in a broad population of patients with severe, uncontrolled asthma, including those with obesity who may have non-eosinophilic disease. The same group reported the post hoc results of the DESTINATION study, a phase 3, multicenter, randomized, double-blind, placebo-controlled extension study that enrolled patients aged 12–80 years with severe, uncontrolled asthma who had participated in the NAVIGATOR trial [63]. Patients who had previously received tezepelumab 210 mg every 4 weeks for 52 weeks continued treatment, while those originally assigned to placebo were re-randomized in a 1:1 ratio to tezepelumab or placebo. AAERs were evaluated over a total treatment period of 104 weeks in patients who received at least one dose of tezepelumab or placebo in NAVIGATOR, stratified by baseline body mass index (BMI): healthy (< 25 kg/m²), overweight (25 to < 30 kg/m²), or obese (≥ 30 kg/m²). Among placebo-treated patients (n = 531), AAERs over 104 weeks increased with higher baseline BMI (< 25 kg/m² 1.78 [95% CI: 1.44–2.21]; 25 to < 30 kg/m² 1.87 [95% CI: 1.48–2.37]; ≥ 30 kg/m² 2.16 [95% CI: 1.74–2.69]). Treatment with tezepelumab (n = 528) significantly reduced AAERs compared with placebo across all BMI categories, with reductions of 58% (95% CI: 42–70), 59% (95% CI: 43–70), and 57% (95% CI: 42–68) in patients with BMI < 25 kg/m², 25 to < 30 kg/m², and ≥ 30 kg/m², respectively. In patients who received tezepelumab only (n = 389) or placebo only (n = 197) throughout both studies, mean (SD) increases from baseline to week 104 were 0.20 (2.03) and 0.43 (2.57) kg/m² for BMI and 0.75 (5.81) and 1.27 (7.10) kg for body weight, respectively. Overall, tezepelumab reduced asthma exacerbations over 2 years regardless of baseline BMI, with minimal changes in body weight. These results were found only as congress abstracts; therefore, they did not fulfill the criteria to be included in our systematic review. Further research is necessary to examine the effects of tezepelumab in patients with asthma and comorbid obesity.

Finally, a recently published study from Gonem et al. [64] involving 1956 patients across the United Kingdom investigated the efficacy of biologic agents in patients that were stratified by BMI categories (healthy, overweight, obese, severely obese). The authors found that patients with increased BMI responded less to biologic agents, in terms of ACQ-6 score, scores and rates of exacerbations, emergency department attendances, and hospital admissions. These results were not drug-specific. Additionally, although FEV₁ improved in all groups, only those with lower BMI had clinically significant improvements. It is noted, however, that obese patients had worse baseline symptoms and scores. This study highlights that obesity is a significant barrier to achieving remission in patients with severe asthma that are treated with a biologic agent.

Overall, the differential response observed across biologic agents suggests that obesity-associated severe asthma may involve mechanisms beyond classic type 2 inflammation, including systemic inflammation driven by adipokines, altered immune signaling, and potential pharmacokinetic limitations of fixed-dose biologics. These findings support the need for BMI-stratified analyses, incorporation of mechanistic biomarkers, and a more individualized approach to biologic selection in patients with severe asthma and comorbid obesity.

Study Limitations

A limitation of this review is the lack of statistical analysis, which prevents quantitative assessment of our findings. Also, no risk of bias assessment was performed. We retrieved only one study on dupilumab and zero on tezepelumab; therefore, some of our research objectives could not be answered. Another study limitation is the limited data on biomarkers’ change in obese patients with severe asthma after treatment: in a study by Yamada et al., 64 individuals with severe asthma were treated with benralizumab. The authors identified five clusters with variability in clinical response. The phenotype cluster with patients with higher BMI had no FEV1 improvement after treatment and was characterized by low T2-inflammation markers [36]. Although the patients within this cluster had higher BMI than in others, they were not obese and only eight patients were included in this cluster. In the study of Ortega et al., obese patients had lower eosinophils and reduced response to treatment, suggesting a phenotype of obesity with less atopy [31].

Conclusions

In conclusion, mepolizumab and benralizumab seem to be more effective in severe asthmatics with lower BMIs, especially in BMI < 30 for mepolizumab and in BMIs < 30–35 for benralizumab. Dupilumab seems to be equally effective across all BMI levels, although we did not find enough articles in our literature review to confidently state it. Regarding reslizumab, a biologic agent that requires weight-based dosing, it may be less effective in obese asthmatics and may be attributed to pharmacokinetics and bioavailability of the biologic. Additionally, regarding tezepelumab, no study was found. While these biologic therapies are an important treatment for patients with asthma, none of them have been heavily studied in patients with asthma and comorbid obesity. Therefore, future research on this topic would help us identify the appropriate biologic agent to use across each BMI category.

Author Contributions

Literature review and data collection: Styliani Papadopoulou and Christodoulos Komiotis, writing of the manuscript: Styliani Papadopoulou, Christodoulos Komiotis, Fotios Drakopanagiotakis, revision and critical input: Fotios Drakopanagiotakis, Stelios Loukides and Paschalis Steiropoulos, conception: Paschalis Steiropoulos. All authors approved and reviewed the final manuscript in line with the ICJME guidelines.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Paschalis Steiropoulos is an Editorial Board member of Pulmonary Therapy. Paschalis Steiropoulos was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Styliani Papadopoulou, Christodoulos Komiotis, Fotios Drakopanagiotakis, and Stelios Loukides have nothing to disclose.

Ethical approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.