The Impact of Obesity on Airway Inflammation, Lung Function and Biologic Treatment in Asthma: A Narrative Review

Introduction

Asthma and obesity have been recognized as a disease burden for centuries. Hippocrates mentioned the effects of obesity over 2000 years ago and he also introduced the term “asthma”.^1–3 Even though the interplay between obesity and respiratory problems was not yet established until 1956, there is historic evidence of physicians treating asthmatic patients with a stricter diet.^3,4 These early observations underscore a long-standing awareness of the potential link between metabolic status and respiratory health. Although the conceptualization of asthma and obesity has evolved substantially since antiquity, these insights highlight that the coexistence of these conditions is far from a modern phenomenon.

Nowadays asthma and obesity are two chronic conditions with increasing global prevalence over the past decades. Around 262 million people were affected by asthma in 2019, while the estimate for obesity prevalence is 890 million globally, and is predicted to keep growing.^5–7 Asthma prevalence in adults in the United States is 7,1% in lean individuals versus 11,1% in obese individuals.⁸ Even more, the prevalence of obesity has increased more in subjects with asthma than in those without.⁹ The parallel increase of these conditions presents a growing clinical challenge as excess adiposity may influence asthma severity, symptom control and response to pharmacotherapy in a bi-directional multifactorial fashion through mechanical, immunologic and inflammatory pathways.^8,10–12

Epidemiological data suggest that individuals with obesity often experience more severe or difficult-to-control asthma, highlighting the importance of understanding disease mechanisms in this subgroup.^13,14 Obesity is a well-established modifier of disease expression and treatment response across multiple chronic conditions, including type 2 diabetes mellitus (DMII), cardiovascular disease, non-alcoholic steatohepatitis, and the metabolic syndrome.^15,16 Shared pathophysiological mechanisms, such as chronic low-grade systemic inflammation, altered adipokine signaling and immune dysregulation, suggest that obesity may similarly influence respiratory disease.^17–19 The recognition of an “obese asthma phenotype” has emerged from this understanding, characterized by increased disease severity, poorer symptom control and reduced responsiveness to conventional therapy.^18,20

Asthma management has undergone substantial evolution. Historically, treatment relied on bronchodilators and corticosteroids, but the past two decades we have seen the emergence of biologic therapies targeting specific inflammatory pathways, including immunoglobulin E (IgE), interleukin (IL)-5, IL-4/13 and thymic stromal lymphopoietin (TSLP).^3,20–23 These agents have significantly improved outcomes in selected patients with severe asthma. However, pivotal clinical trials frequently underrepresent individuals with obesity as shown by Akenroye et al, raising the question whether excess adiposity may modify therapeutic efficacy.²⁴

Since biologic therapies act on specific inflammatory pathways, it is plausible that obesity-related metabolic and inflammatory alterations may alter their effectiveness, as shown in several studies in asthma, but also in inflammatory bowel diseases (IBD).^18,25

Obesity and Airway Inflammation

Asthma is a chronic inflammatory airway disease that is predominantly characterized by type 2 (T2) inflammation, which is present in over 80% of patients. In contrast, asthma associated with obesity is more frequently characterized by a non–type 2, type 1 (T1) and T-helper 17 (Th17)–skewed endotype, diverging from the classical eosinophilic phenotype.²⁶ Consistent with this observation, sputum eosinophils and fractional exhaled nitric oxide (FeNO) are generally lower in obese asthma patients than in non-obese asthma patients.²⁷ However, some studies have reported higher numbers of eosinophils in sputum and submucosa in subsets of obese asthma patients.^28,29 This could probably be related to severity asthma and/or class of obesity, as discussed further on.

Importantly, blood eosinophil counts appear to perform poorly as a biomarker of airway type 2 inflammation in morbidly obese patients. Peters et al demonstrated a strong modifying effect of body mass index (BMI) on the relationship between blood eosinophil counts and sputum type 2 cytokine gene expression (T2GM) While blood eosinophil levels correlated well with sputum T2GM in patients with a BMI < 40 kg/m², this association progressively weakened with increasing BMI and was minimal in morbid obesity.³⁰ In contrast, sputum neutrophils were positively associated with BMI and have been shown to decrease following dietary weight-loss intervention.^31,32

Eosinophils are increasingly recognized as regulators of metabolic homeostasis in adipose tissue, with roles in adipokine secretion and inflammation, suggesting relevance for obesity-related asthma.³³ Adipose tissue eosinophils exhibit distinct transcriptional and functional properties compared with airway eosinophils, which are known to promote airway hyperresponsiveness through neural mechanisms, such as altered sensory signaling, autonomic imbalance or release of neuropeptides.²⁰ These observations underscore the importance of anatomical context and highlight that blood eosinophil counts alone do not adequately reflect tissue-specific eosinophil contributions to asthma pathophysiology.

Interleukin-17 (IL-17) has been associated with corticosteroid resistance by altering the balance between glucocorticoid receptor (GR) isoforms, with dysregulated GR-α and GR-β expression in adipocytes.³⁴ Adipocytes obtained from obese patients cultured in vitro in the presence of IL-17A for 48 hours showed a decrease in GRα/GRβ ratio as compared to adipocytes from lean subjects where GR-α/GR-β ratio was increased following IL-17A and IL-17F stimulation. In addition, IL-17–driven cytokine signaling contributes to the amplification of pro-inflammatory mediator production in obesity. Consistent with these observations, a negative association was demonstrated between BMI and the GR-α/GR-β ratio in the serum of patients with asthma.³⁴ So obesity leads to increased IL-17 signaling that may induce corticosteroid resistance.

Airway hyperresponsiveness (AHR) in obesity has been linked to the expansion of CCR6⁺ type 3 innate lymphoid cells (ILC3s) in bronchoalveolar lavage (BAL) fluid in obese murine models, supporting the existence of an alternative T2-low inflammatory pathway.³⁵ In line with these findings, recent human data indicate increased activation and pulmonary recruitment of total ILCs and ILC3s in obese asthma patients. Moreover, asthma severity has been associated with elevated numbers of activated ILC subsets, particularly Cluster of Differentiation (CD)69⁺, CD161⁺ total ILCs, ILC2s, and ILC3s.³⁶

Visceral adipose tissue (VAT) accumulation in obesity creates a hypoxic microenvironment that promotes differentiation of adipose tissue macrophages (ATMs) toward a pro-inflammatory phenotype. This results in increased secretion of mediators such as interleukin-6 (IL-6) and leptin, which are linked to T-helper 1 (Th1)-mediated immune responses.³⁷ While abdominal circumference rather than overall VAT macrophage burden was found to be most strongly associated with asthma outcomes, obese asthmatic patients exhibited a higher proportion of pro-inflammatory macrophages (M1) ATMs compared with obese non-asthmatic controls. Furthermore, the VAT M1:M2 macrophage ratio was negatively associated with FEV₁ (% predicted).³⁸ Therefore, visceral inflammation with increased pro-inflammatory M1 occurs in obese asthma and may be a determinant of systemic inflammation and asthma severity.

Macrophage infiltration of VAT has also been associated with increased leptin and reduced adiponectin expression independent of BMI.³⁹ Airway epithelial cells express receptors for both adipokines, and airway reactivity has been shown to correlate with visceral fat–derived leptin expression.³⁹ These immunometabolic effects are mediated, at least in part, by insulin resistance and dyslipidemia, hallmark features of obesity.⁴⁰

Obesity may further promote airway dysfunction through increased oxidative stress driven by adipokine imbalance. Elevated leptin levels have shown to induce airway smooth muscle contraction, an effect potentiated by epithelial injury or allergen sensitization.⁴¹ Conversely, adiponectin appears to exert protective effects on human bronchial epithelial cells against mechanical and oxidative injury.⁴² In experimental models of obese asthma, markers of oxidative stress, including 4-hydroxynonenal (4-HNE), isoprostanes, and hydrogen peroxide, were significantly higher in high-fat diet–fed mice than in controls.⁴³ In human studies, plasma 8-isoprostane concentrations were significantly higher in obese children than in lean controls, further supporting a role for systemic oxidative stress in obesity-related asthma.⁴⁴

In summary, asthma is usually linked to type 2 inflammation, but obesity-related asthma often shows a T2-low, type 1–skewed inflammatory profile with lower FeNO, sputum eosinophils, and less reliable blood eosinophil biomarkers. Higher BMI is connected to neutrophilic airway inflammation, increased ILC3 cells, and greater airway hyperresponsiveness. A type 3 (T3) inflammation in obese patients is also proposed, which is mediated by domain-like receptor protein 3 (NLRP3), Th 17 cells and type 17 cytotoxic (tc17) cells.¹⁸ Visceral fat–related immunometabolic disturbance, adipokine imbalance, and oxidative stress likely worsen lung function and asthma severity in obese individuals.

Obesity and Lung Function

Obesity influences asthma through the combined effects of altered respiratory mechanics and obesity-related immunometabolic dysregulation. The accumulation of subcutaneous adipose tissue along the chest wall and visceral fat within the abdomen restricts diaphragmatic excursion and chest wall expansion, resulting in reduced lung compliance and a predominantly restrictive ventilatory pattern.¹⁰ These effects are most pronounced in functional residual capacity (FRC) and expiratory reserve volume (ERV), while total lung capacity (TLC) is only modestly affected.^10,45–47 During dynamic lung function testing, both forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) are reduced, whereas the FEV₁/FVC ratio is generally preserved,^10,47 except in individuals with concomitant metabolic syndrome, underscoring the contribution of systemic metabolic dysfunction.⁴⁸

Given that dynamic hyperinflation with air trapping is already present in up to 81% of non-obese asthma patients,⁴⁹ obesity is expected to further exacerbate air trapping and small airway dysfunction, particularly due to breathing at chronically low lung volumes.^10,46,50 These mechanical effects may amplify airflow limitation and contribute to increased disease severity. Although oxygen saturation may be reduced in obese patients with asthma, particularly in the supine position, diffusion capacity is typically preserved or increased.^51,52 Therefore, hypoxemia is more likely attributable to restrictive lung mechanics and ventilation perfusion mismatch resulting from compression of the dependent lower lung regions.^53,54

Exercise capacity is reduced in obese asthma patients reflected by a decreased six-minute walking distance (6MWD) and Maximum Volume O₂ (VO2max) compared to non-obese asthma patients.⁵⁵ High intensity interval training (HIIT) resulted in greater improvement of cardiopulmonary fitness (VO2max) and a greater reduction of body fat mass compared to traditional exercise.⁵⁶ HIIT also provided sustained improvements in asthma control, body composition and exercise capacity in obese asthmatics that were not optimally controlled.⁴⁶

Importantly, the impact of obesity on lung function is not adequately captured by BMI alone but is strongly influenced by body fat distribution. Elevated visceral to subcutaneous fat area ratio (EV) measured on computed tomography (CT) was associated with decreased airway lumen diameter and a lower FEV1.⁵⁷ Individuals with predominant abdominal (android or “apple-shaped”) adiposity have a higher prevalence of asthma than those with predominantly gluteofemoral (gynoid or “pear-shaped”) fat distribution.^58–60 This association appears particularly pronounced in women, as bronchial provocation studies have demonstrated greater airway hyperresponsiveness and delayed post-challenge recovery in obese women than in men.^50,60

Several mechanisms may underlie obesity-related airway hyperresponsiveness. Breathing at low lung volumes is associated with enhanced bronchial hyperresponsiveness, potentially due to reduced outward tethering forces exerted by the lung parenchyma on the airways and increased airway smooth muscle shortening.^61,62 In addition, closure of peripheral airways during tidal breathing near closing volume, especially in the supine position, leads to airflow limitation and increased peripheral airway resistance.⁵³ Collectively, these mechanical alterations render the lung more susceptible to airway narrowing, creating a functional state that resembles asthma through obesity-related chest wall compression.

These biomechanical changes closely interact with obesity-related immunometabolic dysregulation. Expansion of visceral adipose tissue promotes a pro-inflammatory state with M1 macrophage activation and increased leptin and IL-6 production, driving Th1-skewed inflammation, insulin resistance, and impaired lung function.^38–40 Adipokine imbalance further aggravates airway dysfunction, as leptin increases airway smooth muscle contractility while reduced adiponectin weakens epithelial protection;^41,42 together with obesity-related oxidative stress^43,44 and low lung volume breathing,^53,63 this promotes small airway instability and airway hyperresponsiveness characteristic of obesity-related asthma.

Obesity and Asthma Mutual Influence on Disease Burden

Both, overdiagnosis and underdiagnosis of asthma occur in individuals with morbid obesity. In this population, symptom-based diagnosis alone is unreliable, and objective pulmonary function testing is essential to establish or refute the diagnosis of asthma.⁴⁸ Indeed, approximately one-third of both obese and non-obese individuals with physician-diagnosed asthma do not have asthma when assessed objectively using bronchial provocation or reversibility testing.^64,65 Notably, health-related quality-of-life scores do not differ significantly between subjects with and without demonstrable bronchial hyperresponsiveness, underscoring the limited specificity of symptoms alone in this context.⁶⁵

Conversely, asthma may also remain unrecognised in obese individuals despite the presence of respiratory symptoms. The reasons for underdiagnosis are likely multifactorial. One explanation is symptom misperception at the patient level, whereby dyspnoea and exercise intolerance are attributed to excess body weight rather than to an underlying respiratory disorder, reducing the likelihood of seeking medical attention.⁶⁶ Alternatively, diagnostic misattribution may occur at the physician level, with respiratory complaints being ascribed primarily to obesity rather than prompting objective evaluation for asthma.⁴⁸

Beyond diagnostic challenges, obesity is increasingly recognised as a major disease modifier in asthma. Multiple studies have demonstrated that higher BMI is independently associated with poorer symptomatic control and impaired quality of life. In adult outpatient cohorts, increasing BMI correlates with higher Asthma Control Questionnaire (ACQ) scores and lower Asthma Quality of Life Questionnaire (AQLQ) scores, even after adjustment for age, sex and conventional markers of asthma severity, indicating a greater disease burden in obese compared with lean patients.⁶⁷ These observations are supported by clinical and epidemiological data showing that obesity adversely affects asthma control across phenotypes, mediated by altered lung mechanics, systemic low-grade inflammation and reduced responsiveness to standard therapies.^68,69

In terms of healthcare utilisation, obese individuals with asthma experience more acute exacerbations, emergency department visits and hospital admissions. Importantly, these adverse outcomes appear to improve following substantial weight loss, eg after bariatric surgery, suggesting a causal contribution of adiposity to exacerbation risk and acute care use.⁷⁰ Meta-analytic data further indicate that obese adults with asthma require higher doses of inhaled corticosteroids, short-acting β₂-agonists and systemic corticosteroids than their normal-weight counterparts.⁷¹

In addition to its clinical burden, obesity-related asthma is associated with substantial socioeconomic consequences, in which this association may be bi-directional. Several cohort studies have shown that obese individuals with asthma experience higher rates of work absenteeism and activity limitation compared with normal-weight asthmatics. Increased BMI is independently associated with a greater number of missed workdays, reduced work productivity and higher likelihood of work disability, reflecting both poorer asthma control and the additive impact of obesity-related comorbidities.^67,72 In paediatric populations, obesity similarly amplifies asthma-related school absenteeism, with obese children with asthma missing more school days and reporting greater functional impairment than their lean peers, independent of asthma severity.^73–75

From a health economic perspective, obesity substantially increases the direct and indirect costs of asthma. Obese patients with asthma incur higher healthcare expenditures driven by increased medication use, more frequent physician visits, emergency department presentations and hospitalisations.^68,70,75 Indirect costs, including productivity loss due to absenteeism and presenteeism, further contribute to the societal burden. Importantly, obesity-related asthma has been identified as a key contributor to the overall economic burden of asthma at the population level, accounting for a disproportionate share of costs relative to prevalence.⁷⁶ Interventions that result in sustained weight loss have been associated with reductions in healthcare utilisation, medication requirements and work productivity loss, underscoring the potential societal and economic benefits of targeting obesity as a modifiable trait in asthma management.⁷⁰

Obesity and Treatment Response

Pharmacokinetics and Pharmacodynamics in Obesity

It is well known that obesity can influence many areas of pharmacokinetics (PK) and pharmacodynamics (PD), which makes it challenging to predict how a drug will behave. It has been shown that certain drugs have different levels in people with obesity, while others that share similar traits remain unaffected.⁷⁷ In the following section the basic principles of general drug PK/PD will be briefly described, focusing on how obesity affects the absorption, distribution, metabolism and excretion (ADME) processes.

Absorption: Oral

Obesity influences PK in several ways. Obese people have a higher median gastric pH than lean people.^77,78 Also, the lowest pH measured seems more variable in obese people than in lean people. It is well established that gastric pH can influence bioavailability and thus absorption of several drugs, for example in tyrosine kinase inhibitors (TKI). There is contradictory evidence that gastrointestinal motility and gastric emptying is either increased, not affected or decreased. Increased gastrointestinal motility and emptying could cause lower absorption of oral drugs that are absorbed from the stomach because of less time for solubilization. A similar effect on the gallbladder could explain an enhanced absorption of lipophilic molecules due to improved solubilization in the alkaline bile environment, after oral intake.^77,78 These factors may play a role in the absorption of oral drugs used in obesity-related asthma, as will be mentioned later on.

Absorption: Subcutaneous

Subcutaneously administered large molecule drugs, like biologics, are absorbed slowly into the circulation through the lymphatic system, reaching peak plasma concentrations several days after injection.⁷⁹

There are roughly two different types of distribution of excess adipose tissue in obese patients: gynoid and android obesity. Gynoid obesity manifests as increased subcutaneous fat, juxtaposed to increased visceral fat for android obesity.¹⁰ Visceral fat is connected to metabolic syndrome, and this has been linked to asthma.³⁹ Gynoid obesity might interfere more with absorption of subcutaneous injections in general, because of a larger subcutaneous skin layer from which drug depots are released more slowly than from leaner skin tissue. Gouju et al describe a very limited effect of obesity on absorption of subcutaneous and transdermal applied medication. Although lower values for area under the curve (AUC) were found, efficacy was comparable. These changes in PK are most likely to be influenced by an increase of volume of distribution (Vd) and clearance (Cl).⁷⁸

Distribution

Obesity can affect drug disposition, but no single variable adequately describes the PK changes for all drugs. Alterations in volume of distribution (Vd) are specific to each drug and rely on factors such as proportional fat mass (FM), tissue blood flow, and protein binding. These variables are determined by the physicochemical properties of the drug, including molecular size, degree of ionization, lipid solubility, and permeability across biological membranes.⁸⁰

In obesity, most excess weight is gained as FM and this is stored in adipose tissue. With this weight gain the proportions of the body are altered. Lean body weight (LBW) increases only slightly compared to FM.⁷⁸ The accumulation of FM in adipose tissue therefore lowers the proportional aqueous compartment. Theoretically, Vd should therefore increase namely for lipophilic molecules. For some drugs, such as benzodiazepines this has been observed in research, in which is shown that an increased Vd lead to less clearance and subsequent prolonged half lives.^77,78 However, Smit et al have shown that this is not always the case as propofol and digoxin do not have an increased Vd in obese subjects, because of accumulation in different organs like the heart and liver, instead of FM.⁷⁷

Metabolism/Elimination

In obesity there are often abnormalities in the liver. Obesity can cause liver injury, which can reduce the total clearance capacity of the liver.⁸⁰ However, obesity can also cause an increased liver blood flow through an increased cardiac output.⁷⁷ Thus, if clearance is mainly affected by liver blood flow, elimination is enhanced. However, if clearance is mainly affected by intrinsic metabolizing capacity, then elimination could be decreased because of hepatic impairment.⁷⁷

In general, small drug metabolism consists of two phases: Phase I and Phase II. Enzymes of the cytochrome P450 (CYP) family play an important role in phase I metabolism, mainly modifying the drug by oxidation. Phase II metabolism consists of conjugation reactions, mainly via glucuronidation and sulfation.^77,78 Glucuronidation and sulfation are increased, while CYP3A4 activity is reduced in obese people.^77,80 For drugs that are metabolized by CYP3A4 no changes have been seen in humans. Most likely, clearance of these drugs depends more on liver blood flow than on CYP enzymes. In large molecules, such as biologics, different metabolizing steps are undertaken, as will be discussed later on.

Many drugs are eliminated by the kidneys. It is not completely understood how obesity affects kidney function. Obese subjects most likely exhibit higher total CL, however CL does not linearly increase with total body weight (TBW).⁸⁰

Corticosteroid Efficacy in Obese Patients

It is well known that obese patients are less responsive to corticosteroids, as mentioned in earlier sections. Since corticosteroids are lipophilic substances one might expect that they will accumulate in adipose tissue. However, obese people have higher baseline cortisol levels than normal weight individuals.⁸¹ It is also possible that low grade inflammation lowers the threshold for action by corticosteroids. This might counteract the distribution of corticosteroids towards adipose tissue. Therefore, a decreased response to treatment with corticosteroids is seen in obese asthma patients.^21,71,82 Corticosteroids are partially metabolized by CYP3A4. Chronic low-grade inflammation due to obesity causes a downregulation of CYP3A4. However, this is usually only clinically relevant in cases of morbid obesity. However, also asthma patients with a lower degree of obesity have decreased efficacy of corticosteroids.^10,21,71 It is possible that IL-17 mediated dysregulation of GR-α and GR-β, as mentioned earlier, explains the unresponsiveness of obese asthmatics to corticosteroids.³⁴

Potential Mechanisms for Reduced Biologic Efficacy

The effects of obesity on the pharmacodynamics and kinetics of drugs in general, as previously discussed, are important to consider regarding the potential mechanisms for reduced biologic efficacy in obese asthmatic patients. Reduced biologic efficacy in obese patients has already been shown in other indications like IBD,²⁵ but also recently in severe asthma by Gonem et al.⁸³

Several mechanisms have been proposed. The pharmacokinetic mechanisms contributing to the diminished effectiveness of biologic therapies in obese patients with asthma are not yet fully elucidated. Current consensus suggests that pharmacokinetic alterations alone are unlikely to fully account for reduced biologic efficacy in this group. Nevertheless, several plausible pharmacokinetic mechanisms have been proposed, as shown in Figure 1.

Figure 1 Possible mechanisms for reduced efficacy of biologics in obese asthma patients (A-D). FIGURE MADE WITH BIORENDER.COM. (A) Chronic low grade inflammation and altered immune cell function may lead to reduced biologic drug concentrations at target sites and modify immune responses. Elevated levels of IL-6 and other adipokines, like leptin, that are associated with obesity may modulate immune responses and cause a shift away from T2 -high toward a T2-low inflammatory profile, characterized by increased neutrophilic rather than eosinophilic inflammation pathway. Also, because of the heterogeneity of obesity, there is variable expression of biomarkers such as blood eosinophils and FeNO. This complicates patient selection and monitoring for biologic therapy. (B) Biologics are protected of clearance via neonatal fc receptor (FcRn). In obese patients there is accumulation of several forms of IgG in adipose tissue, which may lead to saturated FcRn’s. This may lead to more clearance of biologics and consequently a reduced drug exposure. (C) Increased body mass and adiposity may theoretically increase the Vd of mAbs possibly resulting in lower plasma peak levels. Despite being engineered for high-affinity binding to target tissue sites, which could imply large apparent Vd in obese patients, mAbs generally do not exhibit extensive tissue distribution in practice. Clinical evidence for this mechanism is limited. Given the molecular size of biologics and their limited distribution in adipose tissue, this mechanism is not most plausible. (D) Because of their large size, biologics are mostly absorbed slowly through lymphatic transport. Obesity increases subcutaneous tissue thickness and alters tissue composition. This may lead to slower and less predictable absorption. Precipitation and catabolism may also play a role in diminished efficacy.

First, increased body mass and adiposity may theoretically increase the volume of distribution of monoclonal antibodies (mAbs), potentially resulting in lower peak and trough serum concentrations when fixed dosing regimens are used. Despite being engineered for high-affinity binding to target tissue sites, which could imply large apparent volumes of distribution, mAbs generally do not exhibit extensive tissue distribution in practice.⁷⁹ This theoretical effect may be particularly relevant for biologics administered independently of body weight, such as, mepolizumab, benralizumab, dupilumab and tezepelumab, and could theoretically lead to subtherapeutic tissue exposure in individuals with high BMI. However, clinical evidence for this mechanism is limited and inconsistent. Moreover, pharmacokinetic studies indicate that bodyweight significantly affects both CL and Vd.⁷⁹ Nevertheless, most pharmacokinetic studies indicate that different mAbs show a lot of similarities in their pharmacokinetic profile.⁸⁴ Therefore, it may be possible that mAbs maintain relatively stable serum concentrations across BMI categories, possibly due to their large molecular size and limited distribution into adipose tissue.

Secondly, obesity increases subcutaneous tissue mass and alters tissue composition, which can slow and reduce the absorption of drugs administered by subcutaneous or intramuscular injection. Slower and less predictable absorption from subcutaneous injections may result in lower and more variable serum concentrations, potentially impacting therapeutic efficacy.^78,85 Local absorption of mAbs is further affected by precipitation and catabolism at the injection site, which can decrease the amount of active drug entering systemic circulation.⁸⁵ Because of their large size, mAbs are mainly absorbed slowly through lymphatic transport, a process that can be further slowed in obesity due to changes in tissue composition.^85–87

Third, obesity-related insulin resistance and metabolic syndrome may affect monoclonal antibody clearance through alterations in the recycling mechanism of neonatal Fc receptor (FcRn).⁸⁸ The accumulation of immunoglobulin G (IgG) in adipose tissue observed in obese patients can potentially alter the clearance of biologics, by increasing tissue-specific IgG accumulation and competition for neonatal FcRn-mediated recycling. In obesity, IgG levels in adipose tissue are markedly elevated, up to 16-fold above plasma levels, due to enhanced FcRn-mediated uptake.^88–90 This may consequently saturate FcRn, which is responsible for protecting IgG and IgG-based biologics from lysosomal degradation and prolonging their half-life.^88–90 When FcRn is saturated, mAbs may undergo increased catabolism, leading to higher clearance and reduced systemic exposure. Nonetheless, robust clinical data supporting a significant role for this mechanism in asthma are currently lacking.

Despite substantial advances in elucidating the pharmacokinetics of mAbs and the factors that influence them, numerous questions remain unresolved. These include data on subcutaneous bioavailability, the precise role of FcRn receptors in mediating efficacy and the influence of molecular characteristics as well as their complex interrelationships.⁹¹ Overall, while pharmacokinetic changes, such as increased Vd and potential alterations in CL, are biologically plausible, the diminished efficacy of biologic therapies in obese patients with asthma is more likely due to alternative mechanisms rather than significant pharmacokinetic abnormalities.^20,92–94

The most plausible mechanism may not be of pharmacokinetic nature. Specifically, obesity is associated not only with changes in drug absorption, distribution, and metabolism, but also with chronic low-grade inflammation and altered immune cell function, as previously discussed. Obesity can thereby potentially reduce biologic drug concentrations at target sites and modify immune responses, which may influence the pharmacodynamic rather than pharmacokinetic effects of biologic therapies.^18,20,92 Elevated levels of circulating IL-6 and other adipokines, like leptin, that are associated with obesity may modulate immune responses in asthma by promoting a shift away from type 2 high (Th2/eosinophilic) inflammation toward non-type 2, T2-low, (Th1/Th17/neutrophilic) inflammatory profile, characterized by increased neutrophilic rather than eosinophilic inflammation pathways.^93,95–98 This immune remodeling is characterized by increased systemic and airway neutrophilia, monocyte and macrophage activation, and Th1 polarization, which can potentially attenuate the efficacy of biologics, as most currently approved biologics target T2-high pathways (eg, IL-5, IgE). However, this represents an indirect effect, rather than a true pharmacokinetic mechanism, these biologics may be less suitable in obese asthma phenotypes, leading to reduced efficacy. Also, this heterogeneity of obese asthma with its variable expression of biomarkers such as blood eosinophils and FeNO and confounding of lung function parameters may also complicate patient selection and monitoring for biologic therapy.^99,100 Traditional biomarkers used for diagnosis and treatment effect may not accurately reflect airway inflammation in obese patients. Therefore, several new biomarkers or targets are being considered in this population, like, IL-6 and IL-33.⁹⁹

Evidence for Biologic Drug Efficacy in Obese Asthma Patients

While these theoretical considerations suggest multiple mechanisms by which obesity may influence biologic treatment response, their clinical relevance ultimately depends on whether such effects are observed in patient outcomes. The following section therefore examines the available clinical evidence on the efficacy per biologic. Table 1 provides a summary of these findings.

Table 1 Overview of the Impact of Obesity on the Efficacy of Asthma Biologics

Omalizumab

Omalizumab was the first biologic registered for treating patients with severe asthma. It exerts its effects by targeting IgE and prohibits binding to mast cells and basophils.⁹⁴ As the first asthma biologic, omalizumab has the most extensive evidence about its effects in patients with obesity-related asthma. Also, omalizumab is unique in its dosing, namely via weight-based dosing and IgE serum levels.⁹⁴

Geng et al found that omalizumab improves lung function, symptom scores, reduces exacerbations, and lowers corticosteroid use in adults with moderate-to-severe allergic asthma, regardless of BMI Notably, obese patients experienced a greater placebo-adjusted reduction in exacerbation rates than normal-weight and overweight (BMI 25–30 kg/m²) groups.¹⁰¹ While increasing BMI showed minor, non-significant improvements in asthma symptoms and quality of life,¹⁰¹ these results align with Oliveira et al, who found significant benefits in lung function, fewer exacerbations, and reduced corticosteroid use with omalizumab in obese patients.¹⁰² Similarly, Özden et al reported omalizumab improved asthma control in this group.¹⁰⁰

In contrast, some observational studies report little or no improvement in asthma control and exacerbation reduction with higher BMI, and some find no significant differences in response based on BMI.^20,21,103 Also, Sposato et al found that obesity was associated with a 3x higher risk of exacerbations and a lower asthma control compared to non-obese patients after more than one year of omalizumab treatment and concluded that obesity reduced omalizumab efficacy.¹⁰⁴ Similarly, Gibson et al, reported that obese patients were significantly less likely to be classified as responders than non-obese patients though among those who did respond, the magnitude of effect was similar between groups.¹⁰⁵ Several other studies also reported that a higher BMI was associated with lower exacerbation reduction or less improvement in asthma control.^106–108 The evidence regarding the efficacy of omalizumab in obese patients therefore is contradictory and warrants further study.

Mepolizumab

Mepolizumab, a biologic for severe eosinophilic asthma that targets IL-5, has shown heterogeneous results on efficacy in obese versus non-obese patients. Some studies find reduced effectiveness in obese individuals, while others report no significant impact of BMI on treatment response.

A meta-analysis of MENSA¹⁰⁹ and MUSCA¹¹⁰ trials found that mepolizumab reduced exacerbations by 49–62% across all BMI categories compared to placebo, despite overlapping confidence intervals. Significant FEV₁ improvements occurred in normal and overweight groups, but not in the obese group. Blood eosinophil reductions were slightly lower in higher BMI groups. Improvements in baseline ACQ-5 scores were consistent across BMI. Albers et al concluded that fixed-dose of 100 mg sc regimen was effective regardless of body weight or BMI.¹¹¹

Several real-world observational studies have reported more pronounced BMI-related differences in treatment response. One study found that BMI ≥30 kg/m² was associated with a poorer ACQ-5 response to mepolizumab (p=0.043) as “super-responders” (upper 25% of ACQ-5 responders) had significantly lower BMI than those in lower quartiles.¹¹² Another study reported that super-responders had a significantly lower BMI and were significantly less likely to have a history of obesity.¹¹³ Da Cunha Fonseca et al observed no significant differences between obese and non-obese patients for most variables, except FVC% predicted, which improved more in non-obese individuals. Both groups showed notable reductions in exacerbations and better asthma control.¹¹⁴ Özden et al found that mepolizumab increased FEV₁ more in non-obese than obese patients, although both groups showed similar gains in asthma control and fewer exacerbations.¹⁰⁰ Regarding clinical remission, Thomas et al reported that the odds of achieving clinical remission decreased by 59% for patients with obesity.¹¹⁵

Some studies report no significant BMI-related differences in mepolizumab response. A meta-analysis by Gibson et al found similar exacerbation rates and ACQ-5 scores in obese and non-obese groups, though only non-obese individuals showed significant FEV₁ improvement.¹¹⁶ Another study reported that mepolizumab reduced exacerbation rates by 47–77% across comorbidity subgroups including obesity, with comparable clinical improvements regardless of obesity status.¹¹⁷ Two other observational studies similarly found no difference in response to mepolizumab by BMI category.^118,119 Although meta-analyses have thoroughly examined data related to mepolizumab, the impact of obesity on its efficacy remains inconclusive.

Benralizumab

Benralizumab is another biologic that targets IL-5, but in a slightly different fashion than mepolizumab and reslizumab. Benralizumab exerts its effect by binding to the alpha subunit of the IL-5 receptor, instead of targeting IL-5 as a ligand.⁹⁴ The evidence regarding benralizumab efficacy in obese versus non-obese patients with severe asthma presents conflicting findings, with some studies demonstrating reduced effectiveness in patients with higher BMI while others report consistent benefits across all weight categories.

In a post-hoc pooled analysis of the SIROCCO¹²⁰ and CALIMA¹²¹ trials, FitzGerald et al found that there were no significant differences in exacerbation rates or FEV₁ improvements among benralizumab patients with BMI ≥35 kg/m², compared to placebo, suggesting impaired efficacy in this severely obese subgroup.¹²² Similarly, Trudo et al found that benralizumab reduced asthma exacerbations and improved lung function for all BMI groups, though benefits were less marked in individuals with obesity.¹²³

Observational studies have shown inconsistent findings on BMI’s effect on benralizumab response, but some suggest higher BMI doubles the risk of a poor outcome.¹²⁴ Another study found that obesity impaired the beneficial effects of benralizumab in patients with severe eosinophilic asthma. A significantly higher proportion of non-obese patients remained completely exacerbation-free compared to those with obesity and morbid obesity, suggesting more efficacy in non-obese patients.¹²⁵ Similarly, findings from the XALOC-1 real-world study showed lower BMI was associated with achieving clinical remission in patients using benralizumab.¹²⁶ Also, Penz et al found that lower BMI at baseline was associated with clinical remission criteria at week 56 in the XALOC-2 prospective real-world study.¹²⁷

In contrast, Menzella et al found that severe annual exacerbation rates decreased considerably across all BMI groups, though the trend suggested diminishing efficacy with increased BMI, the authors concluded that in their Italian real world setting the efficacy of benralizumab was unaffected by obesity.¹²⁸ Also, Kroes et al found no statistically significant difference in BMI between responders and non-responders to benralizumab in the Dutch RAPSODI registry.¹²⁹ Overall, the current evidence highlights a trend toward diminished benralizumab efficacy with increasing BMI, though the magnitude and clinical significance of this effect vary across studies. Further prospective studies are needed to fully elucidate the effect of obesity on the efficacy of benralizumab.

Reslizumab

Reslizumab is the final anti-IL-5 biologic registered for severe asthma, to be covered in this review. The evidence regarding reslizumab’s efficacy in obese patients is limited but suggests benefits across all BMI categories.

In a post-hoc analysis, Nair et al found that both BMI groups (BMI <25 and BMI ≥25) experienced similar reductions in asthma exacerbations with reslizumab, with no significant difference between groups.¹³⁰ Reslizumab is unique among anti-IL-5 biologics for its weight-based dosing, which may explain its consistent efficacy across different BMI groups. One study found that weight-adjusted intravenous reslizumab was more effective than fixed-dose mepolizumab in reducing airway eosinophilia, indicating that pharmacokinetic differences related to bioavailability could drive variable responses to fixed-dose biologics in obese patients.¹³¹

Dupilumab

Dupilumab is the only biologic for severe asthma which exerts its effect by blocking the IL-4 receptor, thereby inhibiting the signaling of both IL-4 and IL-13. In contrast to the other biologics, dupilumab is also registered for a wide array of other indications like eczema, chronic obstructive pulmonary disease (COPD) and chronic rhinosinusitis with nasal polyps (CRSwNP).

The evidence regarding dupilumab efficacy in obese versus non-obese patients with severe asthma largely suggests consistent benefits across BMI categories, although some real-world data indicate potential attenuation in obese patients.

Two post-hoc analyses of the Phase 3 LIBERTY Asthma QUEST¹³² trial found no significant difference in dupilumab treatment response per BMI category. Busse et al reported similar decreases in annualized asthma exacerbation rates after 52 weeks across BMI groups, as well as similar improvements in FEV₁.¹³³ These findings were confirmed by the other post-hoc analyses, in which similar reductions in exacerbation rates and FEV₁ improvements were shown with dupilumab across BMI categories for both the 200 mg and 300 mg dosing regimens.^134,135 Consistent with these findings in severe asthma patients, another study demonstrated that the efficacy of dupilumab in patients with CRSwNP is not affected by BMI, further supporting the notion that dupilumab efficacy is maintained across different body weights.¹³⁶

However, one real-world study suggests a more nuanced picture. Quarato et al followed 20 adults with severe eosinophilic asthma on dupilumab for 24 months and found that obesity was associated with significantly decreased odds of achieving clinical remission.¹³⁷ Given the small sample and unadjusted results, this study should be interpreted with caution.

In summary, while randomized controlled trial data consistently demonstrate that dupilumab effectively reduces exacerbations and improves lung function regardless of BMI, some, albeit limited, real-world evidence suggests that obesity may impair the likelihood of achieving clinical remission. Further long-term studies are needed to clarify the impact of obesity on sustained dupilumab response and whether dose optimization strategies could improve outcomes in obese patients.

Tezepelumab

Approved since 2021, tezepelumab is the newest addition to the severe asthma arsenal.¹⁰³ It works in a distinctly different way compared to other biologics, ie tezepelumab binds upstream of the cascade, to TSLP and thereby prevents further downstream signaling via IL-4, IL-5, IL-13 involving several other signaling pathways, that play a role in T2-high and also in T2-low asthma.¹⁰³ Tezepelumab is the only biologic, to date, with shown benefit for patients with severe asthma involving T2-low pathways.¹⁰³

In a post-hoc pooled analysis of the phase 2b PATHWAY¹³⁸ and phase 3 NAVIGATOR trials,¹³⁹ Corren et al found similar, statistically significant reductions in exacerbations and exacerbation-related hospitalizations after 52 weeks of treatment across BMI groups.¹⁴⁰ Another post-hoc analysis of NAVIGATOR confirmed these findings, by demonstrating similar reductions in asthma exacerbations across all BMI categories.¹⁴¹ Two additional studies confirmed that tezepelumab was effective in lowering the annualized rate of asthma exacerbations, independent of baseline BMI.^142,143

Pharmacokinetic analyses may provide mechanistic support for these clinical findings. Zheng et al demonstrated that while body weight was the most influential covariate on tezepelumab exposure, no significant differences in efficacy or safety were observed across body weight groups in patients receiving the fixed 210 mg sc dose. The authors concluded that the fixed-dose regimen is appropriate for all eligible patients regardless of body weight, as the dose appears to be on the plateau of the exposure-response curve.¹⁴⁴

Emerging real-world data support these trial findings. Two real world studies present results in line with the above-mentioned clinical findings. One study analyzed data from 142 patients (60% obese) treated with tezepelumab, finding no significant differences in treatment responses between obese and non-obese groups. After 12 months, both groups experienced substantial reductions in exacerbation frequency, with similar rates of treatment discontinuation due to adverse effects or lack of efficacy.¹⁴⁵ Worth mentioning, 34,5% of patients in this cohort were T2-low, a population that may be particularly enriched among obese asthmatics and for whom tezepelumab offers a unique therapeutic option.¹⁴⁵ Finally, another study included 129 severe asthma (82 were obese) patients and showed that tezepelumab treatment, irrespective of BMI, was associated with significant reduction in exacerbation rate, improvement asthma control, and even reduction of daily dose of oral corticosteroids.¹⁴⁶

Conclusively, tezepelumab demonstrates consistent efficacy across all BMI categories in both randomized controlled trials (RCT’s) and emerging real-world studies. This distinguishes tezepelumab from other biologics where obesity has been associated with attenuated responses and may make it a particularly appealing possibility for obese patients with severe asthma, especially those T2-low asthma, who may not qualify for or respond optimally to other biologic therapies. Tezepelumab is a relatively new biologic, further real-world evidence will emerge in the future, which will give us more evidence regarding the effects of obesity on its efficacy.

Discussion

Cross-Disease Mechanisms

Anti-Inflammatory and Metabolic Effects of Biologics

Biologics aimed at T2-high inflammation have shown effectiveness, particularly in reducing exacerbation rates among obese individuals with severe asthma. Notably, the underlying mechanisms involve processes that surpass conventional anti-inflammatory pathways. Tezepelumab is unique among asthma biologics for blocking TSLP to reduce inflammation. It shows broad efficacy in severe asthma by suppressing T2 cytokines (IL-4, IL-5, IL-13) and may affect mast cell and airway smooth muscle activation, which could benefit T2-low asthma and other inflammatory diseases. While TSLP is involved in conditions like CRSwNP, COPD, and chronic spontaneous urticaria, tezepelumab is currently approved only for asthma and CRSwNP.¹⁴⁷ Direct metabolic effects of biologics have not yet been investigated, in contrast to indirect metabolic effects. Thus, while anti-TSLP biologics have broad anti-inflammatory effects and potential utility in other inflammatory diseases, their metabolic benefits remain currently unproven.

Reducing Corticosteroid Burden

Although biologics show no direct impact on metabolic outcomes, they may have an indirect effect.¹⁴⁸ Corticosteroids, both oral and inhaled, are widely associated with metabolic issues such as DMII, osteoporosis, and weight gain.¹⁴⁹ It has been shown that the use of biologics can reduce oral corticosteroid (OCS) use in asthmatic patients.^150,151 Regarding ICS use, the SHAMAL study by Jackson et al demonstrated that patients with severe asthma controlled on benralizumab could achieve significant reductions in ICS therapy while maintaining asthma control:¹⁵² 92% of patients successfully reduced their high-dose ICS and 91% remained exacerbation-free during tapering.¹⁵² This finding is particularly relevant for obese asthmatics, who often require higher corticosteroid doses but demonstrate reduced responsiveness.¹⁵³ Although metabolic outcomes were not measured, theoretically, reduced corticosteroid use may improve metabolism and promote weight loss.

Improving Exercise Capacity

While data on exercise capacity specifically in obese asthmatics receiving biologics remain limited, preliminary evidence suggests potential benefits. A pilot study examining physical activity levels in severe asthma patients found that omalizumab and mepolizumab therapy significantly improved daily physical activity compared to conventional therapy.¹⁵⁴ Enhanced functional capacity can be especially significant in cases of obesity-related asthma, as increased mechanical load and physical deconditioning further exacerbate respiratory constraints.

Translational Opportunities: Novel Therapeutic Approaches

Repurposing Metabolic Medication

Repurposing existing medication for new indications is not a novel phenomenon and is widely seen as a durable part of pharmaceutical innovation.¹⁵⁵ The interplay of asthma and metabolic dysfunction has given rise to novel therapeutic possibilities.

In a large cohort study, metformin, widely used in type 2 diabetes treatment, demonstrated approximately 30% reduction in asthma attacks in patients with concurrent diabetes and asthma, with effects independent of glycemic control or weight loss.¹⁵⁶ Also, other studies found benefits of metformin in asthmatic patients, owing its effects most probably to anti-inflammatory mechanisms, as shown in in murine models.^20,156 Remarkably, the addition of GLP-1 receptor agonists (GLP-1RA) to metformin provided an additional 40% reduction in asthma attacks.¹⁵⁶

GLP-1RA, initially registered for DMII and more recently for obesity, especially show promising results in obesity-related asthma through multiple mechanisms beyond just bodyweight reduction. Pre-clinical, clinical and observational studies demonstrate that GLP-1RAs reduce airway inflammation and hyperresponsiveness, through various metabolic and anti-inflammatory mechanisms, particularly in disease processes with metabolic dysregulation.^18,157 A retrospective study in patients with DMII and asthma, GLP-1RA users experienced fewer asthma exacerbations than users of other antidiabetic medications, with differences persisting after adjusting for BMI.¹⁵⁷ These emerging findings suggest GLP-1Ras, administered mostly via sc route but also orally, may represent a novel treatment for asthma associated with metabolic dysfunction, potentially addressing both T2-high and T2-low phenotypes.

Novel Emerging Therapeutic Targets

The convergence of asthma, obesity, and metabolic disorders creates opportunities for integrated therapeutic approaches, not only for repurposing drugs, but also for new targets.

In addition to repurposing GLP-1RAs and metformin, new therapeutic targets are emerging, such as IL-6. Drugs both new and established, like tocilizumab, are under investigation. Other targets include IL-17, IL-23, IL-1-Beta, IL-33 and its receptor, as well as TNF-alpha. Arginine metabolites, including GLP1-arginine advanced glycation end products (AGE), nitro-fatty acids and mitochondrial antioxidants are also being explored, with ongoing clinical trials focused on their potential. Several promising targets are currently under investigation and close to registration, eg itepekimab and astegolimab, both affecting IL-33.^22,23,158

For T2-low asthma, which is frequently associated with obesity and metabolic syndrome, NLRP3 inflammasome inhibitors show promise. Small molecule NLRP3 inhibitors have demonstrated efficacy in reducing neutrophilic airway inflammation and airway hyperresponsiveness in preclinical models. These agents may address the steroid-resistant, neutrophilic inflammation characteristic of obesity-related asthma.^18,20,22,159 Also, imatinib, a TKI, is currently under investigation in T2-low asthma patients.²²

Other therapies are also under scrutiny in this population, like allergen immunotherapy, probiotics, but also bariatric surgery, which has shown to reduce asthma medication, for at least 60 months after surgery.^18,160 But also emerging weight-loss drugs, similar to GLP-1RA, that work like di- or triagonists eg tirzepatide, may have huge impact on this population.^18,20

Pharmacologic Drug Delivery Innovations

The choice between systemic and inhaled delivery carries important implications. While current biologics require subcutaneous or intravenous administration, which may be altered in obese patients, inhaled formulations like ecleralimab, the first inhaled anti-TSLP antibody, may offer improved tissue penetration and reduced systemic adverse events.¹⁰³ Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation in mild atopic asthma. This approach offers potential advantages of direct lung targeting with reduced systemic exposure, though efficacy in obesity-related asthma requires investigation.¹⁶¹ Another state of the art formulation is the formulation of the drug lunsekimig, with NANOBODY technology and bispecific inhibition of TSLP and IL-13, which promises enhanced efficacy through improved tissue penetration.¹⁶²

Limitations of Current Evidence

The current evidence for biologics in severe asthma patients with obesity suffers from several limitations. Most data derive from retrospective analyses or post-hoc subgroup analyses of clinical trials, with obese patients not principally considered in trial design.^20,24 Real-world studies and registry data provide valuable insights but lack the rigor of prospective trials.⁸³ Sample sizes in obesity-specific analyses remain small and heterogeneous, limiting generalizability.

Standardized metabolic endpoints are notably absent from asthma trials. Studies rarely incorporate measures of insulin resistance, adipokine profiles, or metabolic syndrome components, hampering our understanding of how metabolic dysfunction modulates biologic efficacy. Future research should elucidate cellular and metabolic functions in the obesity-asthma relationship to optimize treatment selection. Head-to-head comparisons of biologics and biomarker driven research in patients eligible for multiple agents are needed to guide personalized therapy.

Conclusion

Obesity and asthma comorbidity create a difficult-to-treat phenotype, driven by complex interactions between systemic inflammation, mechanical factors of adiposity, and metabolic dysfunction. These factors complicate disease management, with unresolved questions about disease drivers and the impact of weight loss. While losing weight can help, it is often hindered by asthma symptoms.

Biologics such as dupilumab and especially tezepelumab show potential in treating asthma in obese patients, but more studies tailored to obese patients are needed to optimise dosing and delivery. Obesity-induced changes in pharmacokinetics, pharmacodynamics and immune function may affect efficacy of biologics and require dedicated research.

Future trials should assess both respiratory and metabolic outcomes; GLP-1RA drugs illustrate this approach. This therapeutic duality hints at deeper mechanistic connections awaiting further investigation. But also emerging new targets and pharmaceutical formulations currently being investigated will hopefully be of great value in this population.

The path forward requires abandoning separate approaches that treat asthma and obesity as isolated entities. Precision medicine should guide therapy selection, integrating immunologic and metabolic profiles to tailor interventions for each patient type. Managing obesity-related asthma requires unified strategies addressing both airway and metabolic issues, improved biomarker research and personalized biologic treatments to transform this complex condition into a manageable multisystem disease.