Salbutamol

Serious harms

Salbutamol, albuterol in the US, is prescribed for narrowed airways in asthma and other reversible airway disease ¹.

Condition	How often	Who is at risk	Source
Paradoxical bronchospasm; anaphylaxis	Not estimated	Often first use of a new canister	¹
Lactic acidosis	40 of 154 children (26%) at 4 hours; lactate ≥5.0 mmol/l in 97 of 324 (30%) in asthma trials	Nebulised delivery, adjusted OR 10	²³
Hypokalaemia	168 of 433 children (38.8%); 5 below 2.5 mEq/l	Nebulised route, emergency or intensive care, age above 5	⁴
Atrial fibrillation, supraventricular tachycardia, QTc prolongation	Not estimated	Loop or thiazide diuretics; high doses	⁵¹
Ketoacidosis	Not estimated	Diabetes; large intravenous doses	¹
Overdose, excessive use: seizures, arrhythmia, cardiac arrest, death	Not estimated; heart rate above 200/min in isolated cases aged 2 to 12	Home nebuliser use; methylxanthines (animal data)	¹⁵
Death with 3 or more canisters a year (association)	14.8% against 12.6% over 5 years; 59,533 aged 65 to 99	6 or more canisters: HR 1.56	⁶
Maternal pulmonary oedema and infarction; fetal cardiomegaly	EU 2013: 98 cardiovascular reports, 2 fatal; 8 infant deaths	Use to delay labour, rising with duration	⁷⁸
Stevens-Johnson syndrome, erythema multiforme	Rare	Children taking tablets	⁹

Potassium possibly shifts into cells; the fall is usually transient, lowest a mean 12 hours after presentation ¹⁴. In 47 reported patients, lactate fell by 3.0 mmol/l or more, or to 2.5 mmol/l or less, after a median 13 hours (3 to 56) ³. Excessive-use deaths are suspected to follow cardiac arrest in a severe attack with hypoxia ¹. None of 12 placebo-controlled trials of delaying labour reported cardiac arrest or intensive care admission ¹⁰.

Other pathways it affects

The receptor salbutamol binds is found in many tissues besides airway muscle ¹⁸¹.

Lung: epithelium, glands, vessels and immune cells express it; an anti-inflammatory effect is not indicated ¹⁸.
Heart: beta2 receptors are 10% to 50% of cardiac beta-adrenoceptors; protein kinase A phosphorylates phospholamban, RyR2 and troponin I, and cyclic AMP activates the HCN4 pacemaker channel ¹¹⁹.
Muscle and potassium (animal): in rat muscle at high potassium, salbutamol with warming and lactic acid restored force, recovery depending on the Na+-K+ pump ²⁰.

Transport cycle of the Na+/K+-ATPasePlasma membrane

E1E1·3Na+Na+/K+-ATPase (catalytic α, auxiliary β)Cytoplasmic gate open; 3 Na+ bind from the cytosol
E1·3Na+E1P(3Na+)Na+/K+-ATPase (catalytic α, auxiliary β)ATP → ADP, Mg2+ATP phosphorylates the conserved aspartate; 3 Na+ occluded
E1P(3Na+)E2PNa+/K+-ATPase (catalytic α, auxiliary β)Extracellular gate opens; affinity falls and 3 Na+ leave the cell
E2PE2P·2K+Na+/K+-ATPase (catalytic α, auxiliary β)Ouabain and other cardiotonic steroids2 K+ bind from outside; K+ antagonises ouabain binding
E2P·2K+E2(2K+)Na+/K+-ATPase (catalytic α, auxiliary β)H2O → phosphateExtracellular gate closes; aspartyl phosphate hydrolysed; 2 K+ occluded
E2(2K+)E1Na+/K+-ATPase (catalytic α, auxiliary β)ATP bound, not hydrolysedNucleotide opens the cytoplasmic gate; 2 K+ released into the cytosol

Muscle and heart (healthy people): oral 16 mg daily for 11 weeks in 26 trained men added 1.8 kg lean mass, blunted endurance gains and thickened heart walls on echocardiography, not magnetic resonance ²¹; inhaled doses lowered fat mass in women only ²².
Glucose and lactate (people): glucose exceeded 11 mmol/l in 56 of 154 children, 95% of all 154 also given corticosteroid; lactate is ascribed to stimulated glycolysis, fatty acids inhibiting pyruvate dehydrogenase ²³.

GlycolysisCytosol

Glucose
Hexokinases 1–3 (HK1–HK3); glucokinase (GCK) in liver and β cellsATP to ADPGlucose 6-phosphate (HK1–HK3)Irreversible; GCK has a higher Km and less product inhibition
Glucose 6-phosphate
Glucose-6-phosphate isomerase (GPI)
Fructose 6-phosphate
Phosphofructokinase-1 (PFKL, PFKM, PFKP)ATP to ADP, Mg2+ATPCitrateCommitted step; AMP, ADP and fructose 2,6-bisphosphate activate
Fructose 1,6-bisphosphate
Aldolase (ALDOA, ALDOB, ALDOC)Also yields DHAP, which TPI1 isomerises; later steps run twice per glucose
Glyceraldehyde 3-phosphate
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)NAD+ to NADH, Phosphate
1,3-Bisphosphoglycerate
Phosphoglycerate kinase 1 (PGK1)ADP to ATP, Mg2+First substrate-level phosphorylation
3-Phosphoglycerate
Phosphoglycerate mutase (PGAM1, PGAM2)2,3-Bisphosphoglycerate (primer)
2-Phosphoglycerate
Enolase (ENO1, ENO2, ENO3)Mg2+Releases water
Phosphoenolpyruvate
Pyruvate kinase (PKLR in liver and red cells; PKM)ADP to ATP, Mg2+, K+Irreversible; fructose 1,6-bisphosphate activates PKLR and PKM2
Pyruvate

Brain (cells, animals): salbutamol lowered alpha-synuclein through reduced H3K27 acetylation at SNCA; clenbuterol protected dopaminergic neurons in MPTP-treated mice ²³.
Ovary and fetus (animals): dietary doses caused benign mesovarian leiomyomas in rats, subcutaneous doses cleft palate in 4.5% and 9.3% of mouse fetuses ¹.

What it is for and how it works

Inhaled salbutamol relaxes the muscle of narrowed airways within 5 minutes, for 3 to 6 hours ¹⁸. Its receptor couples to Gs; adenylyl cyclase forms cyclic AMP, and protein kinase A lowers myosin phosphorylation and cytosolic calcium ¹⁸¹.

Beta2-adrenoceptor signalling in airway smooth muscleAirway smooth muscle cell

ATP
Adenylyl cyclaseMg2+Gs alpha from the agonist-bound beta2 adrenoceptor activates it
Cyclic AMP
Protein kinase A holoenzymecAMP binds the regulatory subunits, which release the catalytic ones
Free protein kinase A catalytic subunits
Protein kinase A catalytic subunitATP, Mg2+KCa channels and heat shock protein 20 are further substrates
Phosphorylated myosin light-chain kinase
several stepsLess phosphorylation of the myosin regulatory light chain
Relaxed airway smooth muscle

Receptor kinases and arrestin uncouple the occupied receptor from Gs, desensitising airway cells, tissue and mice ¹⁸²⁶; in people, bronchoprotection fell by 0.75 doubling doses with regular use (3 trials, 50 people) ²⁷.

In the body

More salbutamol reaches the blood from a tablet than from inhaled doses ¹⁹.

Peak plasma levels were about 3 ng/ml after 12 inhaled puffs and 18 ng/ml after a 4 mg tablet; half-life is about 4.6 to 6 hours ¹⁹. SULT1A3, most active in the small intestine, sulfates it ³¹. Nebulised doses above 3 mg raised children’s heart rate by more than 10% without more bronchodilation ⁵. Beta-blockers may provoke severe bronchospasm; loop or thiazide diuretics can worsen hypokalaemia and ECG change ¹.

Genetic variation

Routine genetic testing for this drug class is judged unwarranted by a pharmacology reference ¹⁸.

Benefit against harm

Salbutamol relieves symptoms but leaves airway inflammation untreated ¹⁸³³.

US approval rests on FEV1 over 2 to 12 weeks, with safety data from 248 recipients ¹.

Group	Benefit	Serious harm
Stable asthma: regular against as-needed use	Exacerbations unchanged (OR 0.86, 2922 people) ²⁷	Tremor OR 13.47; few trials reported adverse events ²⁷
Mild asthma, up to 52 weeks: reliever alone against as-needed budesonide-formoterol	Mortality and quality of life not different ³⁴	From age 12, exacerbations needing systemic corticosteroid 109 against 52 per 1000, one more per 18 ³⁴; aged 5 to 15, attacks 0.41 against 0.23 per child-year ³⁵
Children after a beclomethasone run-in excluding 555 of 843: salbutamol alone against daily beclomethasone, 44 weeks	Growth 1.1 cm greater ³⁶	First exacerbation 49% against 28%, one more per 5 ³⁶

AstraZeneca wholly or partly funded both trials behind the figures from age 12 ³⁴.

Without the medicine

In a randomised trial of 655 adults, breathing retraining raised asthma quality-of-life scores by 0.28 and 0.24 at 12 months; attacks were not significantly fewer (9% and 11% against 15%) ³⁷.

How the recommendations were set

Reliever limits were set from studies linking heavy use with severe attacks and death ³³³⁸.

Among 195 UK asthma deaths, 65 of 165 (39%) were issued more than 12 relievers in the final year, without a comparison group ³⁸. In 2023 the EU warned that overuse may raise the risk of severe exacerbations and death, setting re-evaluation above twice-weekly use ³³.

Stopping

In two trials, airway calibre and responsiveness did not differ significantly 1 and 4 weeks after regular salbutamol was stopped ²⁷.

Needing more doses than usual calls for re-evaluation ¹.

A prescription is changed together with the prescriber.

References

Regulator
GlaxoSmithKline LLC. VENTOLIN HFA (albuterol sulfate inhalation aerosol), for oral inhalation use: full prescribing information US Food and Drug Administration, approved prescribing information, initial US approval 1981; DailyMed structured product labelling version 30, published 6 April 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d92c5d6b-ff10-4087-36a2-1cfc464cb967
Funding and finding
Funding
GlaxoSmithKline LLC holds the application and submits the labelling text; the US Food and Drug Administration approves it.
Finding
Indicated for treatment or prevention of bronchospasm in adult and paediatric patients aged 4 years and older with reversible obstructive airway disease, and for prevention of exercise-induced bronchospasm in the same ages; the dose is 2 inhalations every 4 to 6 hours, or 15 to 30 minutes before exercise, and each actuation delivers 108 µg of albuterol sulfate from the mouthpiece, equivalent to 90 µg of albuterol base. Activation of beta2-adrenergic receptors on airway smooth muscle activates adenyl cyclase and raises intracellular cyclic AMP, which activates protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation; albuterol relaxes the smooth muscle of all airways from the trachea to the terminal bronchioles and acts as a functional antagonist, relaxing the airway irrespective of the spasmogen; increased cyclic AMP concentrations are also associated with inhibition of release of mediators from mast cells in the airway. Beta2-adrenoceptors comprise 10% to 50% of the total beta-adrenoceptors of the human heart. Systemic levels are low after inhalation of recommended doses: in 12 healthy subjects given 1080 µg of albuterol base, mean peak plasma concentration was approximately 3 ng/ml, time to peak 0.42 hours against 0.17 hours for a CFC-propelled inhaler, and the apparent terminal plasma half-life approximately 4.6 hours. Beta-adrenergic agonists may produce significant hypokalaemia, possibly through intracellular shunting, with potential adverse cardiovascular effects; the decrease in serum potassium is usually transient and does not require supplementation. Hypokalaemia and changes in blood glucose may occur; caution is advised in diabetes mellitus, and large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. Signs of overdosage include seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, tremor, muscle cramps, hyperglycaemia, hypokalaemia and metabolic acidosis. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma; the exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. A need for more doses than usual may mark destabilisation of asthma and requires re-evaluation of the patient and the treatment regimen, with special consideration of the possible need for anti-inflammatory treatment; beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Paradoxical bronchospasm may be life threatening and frequently occurs with the first use of a new canister. In 202 adults and adolescents treated with 2 inhalations four times daily for 12 weeks, adverse reactions with an incidence of 3% or more and more common than placebo were throat irritation (10% against 7%), viral respiratory infections (7% against 4%), upper respiratory inflammation (5% against 2%), cough (5% against 2%) and musculoskeletal pain (5% against 4%).
Independent research
Ruman-Colombier M, Rochat Guignard I, Di Paolo ER, Gehri M, Pauchard JY. Prevalence and risk factors of lactic acidosis in children with acute moderate and severe asthma, a prospective observational study European Journal of Pediatrics, 2021.
doi:10.1007/s00431-020-03834-x PubMed 33089387
Funding and finding
Participants
154
Follow-up
capillary blood gas 4 h after the first dose of salbutamol in hospital
Funding
Open access funding provided by University of Lausanne. Conflict of interest: the authors declare that they have no conflict of interest.
Finding
Four hours after the first hospital dose of salbutamol, 134 of 154 children (87%) had lactate above 2.2 mmol/l and 40 (26%) above 5 mmol/l with an anion gap of at least 16 mmol/l, of whom 6 (4%) had a pH below 7.35. Hyperglycaemia above 11 mmol/l was recorded in 56 children (36%); 146 (95%) had received corticosteroids, at a mean dose of 1.85 ± 0.75 mg/kg, and 108 (70%) received salbutamol by nebuliser. Adjusted odds ratios for lactic acidosis were 10 (95% CI 2.3 to 47) for nebulised rather than inhaler delivery, 3.2 (1.4 to 7.4) for hyperglycaemia and 2.8 (1.2 to 6.6) for age above 6 years. Mean salbutamol dose was 11.8 mg (SD 9.8) below 6 years and 12.3 mg (SD 10.5) above 6 years. The authors ascribe the lactate rise to beta2-adrenergic stimulation of glycogenolysis, gluconeogenesis and glycolysis together with lipolysis, free fatty acids inhibiting pyruvate dehydrogenase and so favouring conversion of pyruvate to lactate.
Independent research
Liedtke AG, Lava SAG, Milani GP, Agostoni C, Gilardi V, Bianchetti MG, et al. Selective ß2-Adrenoceptor Agonists and Relevant Hyperlactatemia: Systematic Review and Meta-Analysis Journal of Clinical Medicine, 2019.
doi:10.3390/jcm9010071 PubMed 31892109
Funding and finding
Funding
This research received no external funding.
Finding
Forty-seven individual patients (46 on a short-acting agonist) had lactate of 5.0 mmol/l or more, which fell by 3.0 mmol/l or more, or to 2.5 mmol/l or less, 3 to 56 h (median 13 h) after stopping (24), reducing (17) or continuing (6) the agonist. In 12 clinical trials, lactate of 5.0 mmol/l or more occurred in 103 of 426 patients (24%): 97 of 324 with acute asthma (30%; 63 of 212 aged 18 or under and 34 of 112 older) and 6 of 102 women in premature labour (5.9%). In healthy volunteers albuterol raised lactate by about 2.0 mmol/l intravenously (n = 4) and 0.8 mmol/l nebulised (n = 14). Lactate correlated with intravenous albuterol dose in 42 children and with circulating albuterol in 65 adults. The authors ascribe the rise to beta2-stimulated aerobic glycolysis in skeletal muscle and note that tachypnoea from lactic acidosis can be misread as worsening asthma; all but one report lacked a measure of attack severity.
Independent research
Hung J, Kraft T, Seefried B, Johnson DW, Bailey M, Dersch-Mills D. Potassium disturbance associated with an inpatient childhood asthma pathway Paediatrics & Child Health, 2020.
doi:10.1093/pch/pxz131 PubMed 33354265
Funding and finding
Participants
433
Follow-up
hospital admission; mean time to lowest potassium 12.0 h after emergency presentation
Funding
There are no funders to report for this submission.
Finding
Hypokalaemia (potassium below 3.5 mEq/l) occurred in 168 of 433 children (38.8%): mild (3.0 to 3.4) in 120, moderate (2.5 to 2.9) in 43 and severe (below 2.5) in 5. Nebulised rather than inhaled salbutamol, location in the emergency department or intensive care unit and age above 5 years remained associated with hypokalaemia after adjustment; the authors note these factors may mark higher salbutamol doses.
Regulator
Ritedose Pharmaceuticals, LLC. Albuterol Inhalation Solution, USP 0.083%: prescribing information US Food and Drug Administration, approved labelling; DailyMed structured product labelling version 20, published 30 April 2026, text dated February 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b72742df-1a6b-4483-aff3-3e79db5e015d
Funding and finding
Funding
Ritedose Pharmaceuticals, LLC markets the product and submits the labelling text; the US Food and Drug Administration approves it.
Finding
Indicated for relief of bronchospasm from 2 years of age; usual dose 2.5 mg three to four times daily by nebulisation. In asthmatic patients less than 20% of a nebulised or IPPB dose was absorbed, the remainder being recovered from the apparatus and expired air; after 3 mg nebulised, the maximum plasma level at 0.5 h was 2.1 ng/ml (range 1.4 to 3.2). In children, single doses of 3, 4 or 10 mg gave peak expiratory flow improvement comparable to 2 mg, but doses above 3 mg raised heart rate by more than 10%. Repeated dosing with 0.15 mg/kg in initially normokalaemic children aged 5 to 17 years was associated with an asymptomatic 20% to 25% fall in serum potassium. In clinical trials in 135 patients, drug-related effects were tremor 20%, dizziness 7%, nervousness 4%, headache 3%, nausea 4%, bronchospasm 8%, tachycardia 1% and hypertension 1%. Fatalities have been reported with excessive use of inhaled sympathomimetics and with home use of nebulisers. Postmarketing reports include urticaria, angioedema, oropharyngeal oedema, arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles, and metabolic acidosis. In isolated overdosage cases in children aged 2 to 12 years, heart rates above 200 beats/min were observed.
Independent research
To T, Zhu J, Terebessy E, Zhang K, Gershon AS, Licskai C. Is overreliance on short-acting β2-agonists associated with health risks in the older asthma population? ERJ Open Research, 2022.
doi:10.1183/23120541.00032-2022 PubMed 35350274
Funding and finding
Participants
59,533
Follow-up
up to 5 years after a 1-year baseline, to 31 March 2021
Funding
Supported by the SickKids Research Institute, Toronto; T. To is funded by a Canadian Institutes of Health Research Tier 1 Canada Research Chair in Asthma; supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The supporters and funders had no role in study design, data collection, analysis, interpretation, writing or the decision to submit.
In-kind support
IQVIA Solutions Canada Inc. provided use of its Drug Information File.
Finding
8465 people (14.2%) filled 3 or more SABA canisters in the baseline year. Over 5 years 7684 (12.9%) died: 14.8% of those with 3 or more canisters against 12.6% of those with fewer. Against 1 to 2 canisters a year, adjusted hazard ratios for all-cause death were 1.11 (95% CI 1.02 to 1.22) for 3 to 5 canisters and 1.56 (1.41 to 1.71) for 6 or more, adjusted for age, sex, comorbidities, baseline exacerbations, marginalisation, rurality and baseline asthma medication. Severe exacerbations (emergency visit or admission) occurred in 7.5% against 2.1%, adjusted hazard ratios 1.59 (1.40 to 1.82) and 2.26 (1.96 to 2.60). Inhaled corticosteroid at baseline appeared to mitigate but not eliminate the association.
Regulator
European Medicines Agency; Coordination Group for Mutual Recognition and Decentralised Procedures – Human. Short-acting beta-agonists: Article 31 referral. Restrictions on use of short-acting beta-agonists in obstetric indications – CMDh endorses PRAC recommendations European Medicines Agency, procedure EMEA/H/A-31/1347, reference EMA/565019/2013, first published 25 October 2013, with Annex II scientific conclusions, 2013.
https://www.ema.europa.eu/en/medicines/human/referrals/short-acting-beta-agonists
Funding and finding
Funding
European Medicines Agency and the EU national competent authorities; review initiated on 27 November 2012 at the request of the Hungarian medicines agency
Finding
The review covered fenoterol, hexoprenaline, isoxsuprine, ritodrine, salbutamol and terbutaline in obstetric use, with data from clinical studies, post-marketing reports and the literature; no inhaled formulation was authorised for obstetric indications. For salbutamol, 98 reports with cardiovascular events were identified, most of them arrhythmias such as tachycardia or palpitations; two reports of tachycardia were fatal; pulmonary oedema contributed to several events, one with cardiomegaly after five weeks of tablets; eight infant fatalities were noted, two with pulmonary oedema and cardiovascular events; reports involved both intravenous and oral salbutamol. PRAC concluded that oral and suppository forms of short-acting beta-agonists carry serious, dose-dependent cardiovascular risk to mother and fetus, mostly with prolonged use, with very limited efficacy data, and should no longer be used in any obstetric indication; products authorised only for obstetric use were to be revoked and recalled by 25 November 2013. Injectable forms were restricted to 48 hours between 22 and 37 weeks of gestation under specialist supervision, contraindicated with pre-existing ischaemic heart disease or significant risk factors for it, with monitoring of blood pressure, heart rate, electrocardiogram, electrolyte and fluid balance, glucose, lactate and potassium. PRAC recommendation 5 September 2013; CMDh position 23 October 2013.
Regulator
Medicines and Healthcare products Regulatory Agency. Short-acting β2 agonists: restricted use for tocolysis in premature labour MHRA Drug Safety Update, volume 7, issue 4, November 2013: A3 (republished on GOV.UK 11 December 2014), 2013.
https://www.gov.uk/drug-safety-update/short-acting-2-agonists-restricted-use-for-tocolysis-in-premature-labour
Funding and finding
Funding
Medicines and Healthcare products Regulatory Agency
Finding
Oral salbutamol and terbutaline preparations were found ineffective for acute tocolysis and not consistently effective at maintaining uterine quiescence, and maintenance tocolysis had no significant effect on perinatal morbidity and mortality. Use of oral short-acting beta2-agonists has been associated with serious and potentially fatal cardiovascular events such as myocardial infarction and pulmonary oedema in the mother and cardiomegaly in the fetus, increasing with duration of use; the obstetric indications were removed from oral products. Parenteral use is limited to 48 hours under specialist supervision, not initiated below 22 weeks or in women with risk factors for ischaemic heart disease or conditions such as pulmonary hypertension, hypertrophic obstructive cardiomyopathy or aortic stenosis; the risk of serious adverse events increases with dose, and blood pressure, heart rate, electrocardiogram, electrolyte and fluid balance, glucose, lactate and potassium are to be monitored.
Regulator
Sun Pharmaceutical Industries, Inc. Albuterol Tablets, USP: prescribing information US Food and Drug Administration, approved labelling; DailyMed structured product labelling version 7, published 18 March 2026, text revised 03/2023, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=87b8cd3c-2849-4b50-b63e-9ea379165c07
Funding and finding
Funding
Sun Pharmaceutical Industries, Inc. distributes the product and submits the labelling text; the US Food and Drug Administration approves it.
Finding
Indicated for relief of bronchospasm in adults and children 6 years and older; usual adult dose 2 or 4 mg three or four times daily, total daily dose not above 32 mg. After one 4 mg tablet in normal volunteers, maximum plasma albuterol was about 18 ng/ml within 2 hours, with a half-life of about 5 hours. The most frequent adverse reactions in clinical trials were nervousness 20%, tremor 20%, headache 7%, tachycardia 5%, palpitations 5% and muscle cramps 3%. Warnings: paradoxical bronchospasm that may be life threatening; clinically significant cardiovascular effects, with electrocardiographic T-wave flattening, QTc prolongation and ST depression reported; immediate hypersensitivity reactions; rare erythema multiforme and Stevens-Johnson syndrome with oral albuterol in children; significant hypokalaemia; aggravation of pre-existing diabetes mellitus and ketoacidosis by large intravenous doses. Albuterol is not approved for preterm labour, and serious adverse reactions including maternal pulmonary oedema have been reported during or after treatment of premature labour with beta2-agonists including albuterol. Overdosage may produce seizures, angina, hypertension or hypotension, tachycardia up to 200 beats/min and arrhythmias; cardiac arrest and death may be associated with abuse. Subcutaneous albuterol produced cleft palate in 5 of 111 (4.5%) and 10 of 108 (9.3%) mouse fetuses at 0.25 and 2.5 mg/kg; congenital anomalies including cleft palate and limb defects have been rarely reported in offspring of treated patients without a consistent pattern.
Independent research
Neilson JP, West HM, Dowswell T. Betamimetics for inhibiting preterm labour Cochrane Database of Systematic Reviews, 2014.
doi:10.1002/14651858.CD004352.pub3 PubMed 24500892
Funding and finding
Participants
1,367
Funding
Internal sources: University of Liverpool, UK. External sources: UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization.
Finding
Against placebo, betamimetics reduced births within 48 hours (RR 0.68, 95% CI 0.53 to 0.88; 10 trials, 1209 women) and within 7 days (RR 0.80, 0.65 to 0.98), without reducing preterm birth before 37 weeks (RR 0.95, 0.88 to 1.03), perinatal death (RR 0.84, 0.46 to 1.55) or neonatal death (RR 0.90, 0.27 to 3.00). Maternal harms: cessation of treatment for adverse effects RR 11.38 (5.21 to 24.86; 5 trials, 1081 women), chest pain 11.29 (3.81 to 33.46; 2 trials, 814 women), dyspnoea 3.86 (2.21 to 6.77), palpitation 9.91 (6.46 to 15.20; 5 trials, 1089 women), tremor 10.74 (6.20 to 18.59; 1 trial, 708 women), headache 4.07 (2.60 to 6.35), hypokalaemia 6.07 (4.00 to 9.20; 1 trial, 708 women), hyperglycaemia 2.90 (2.05 to 4.09) and nausea or vomiting 1.76 (1.29 to 2.42); fetal tachycardia was also more frequent. Maternal pulmonary oedema occurred once across three trials (RR 3.03, 0.12 to 74.23) and myocardial ischaemia RR 12.53 (0.72 to 216.91; 1 trial, 106 women); two trials reported maternal death (none), and cardiac arrest, respiratory arrest and intensive care admission were reported in no trial. In one trial of 200 women, terbutaline produced fewer side effects than salbutamol (RR 0.54, 0.42 to 0.70) and less tachycardia (RR 0.48, 0.30 to 0.75).
Funding unknown
Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis Chest, 2004.
doi:10.1378/chest.125.6.2309 PubMed 15189956
Funding and finding
Funding
not read: the full text requires a subscription; the archived journal page shows the abstract and affiliations (Santa Clara Valley Medical Center; Cornell University) without a funding statement.
Finding
A single dose of beta2-agonist raised heart rate by 9.12 beats/min (95% CI 5.32 to 12.92) and lowered potassium by 0.36 mmol/l (0.18 to 0.54) against placebo. In trials of 3 days to 1 year, beta2-agonists increased the risk of a cardiovascular event (sinus or ventricular tachycardia, syncope, atrial fibrillation, heart failure, myocardial infarction, cardiac arrest or sudden death): RR 2.54 (1.59 to 4.05); sinus tachycardia alone RR 3.06 (1.70 to 5.50), all other events RR 1.66 (0.76 to 3.6). Longer trials were included only if they reported at least one adverse event.
Funding unknown
Amegadzie JE, Gamble JM, Farrell J, Gao Z. Association between Inhaled β2-agonists Initiation and Risk of Major Adverse Cardiovascular Events: A Population-based Nested Case-Control Study International Journal of Chronic Obstructive Pulmonary Disease, 2022.
doi:10.2147/COPD.S358927 PubMed 35645559
Funding and finding
Participants
180,567
Funding
This work was supported by a research grant from Canada Research Respiratory Network (CRRN), Ottawa, Canada (Young Investigator Award, 2017). The study funder was not involved in the study design or the writing of the protocol. The network's partnerships page lists CIHR, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis as CRRN funding partners in 2017 (https://web.archive.org/web/20170628185311/http://respiratoryresearchnetwork.ca/partnerships) and AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Novartis and Sanofi among current or previous partners in 2026 (https://respiratoryresearchnetwork.ca/partnerships/), so freedom of the grant from industry money cannot be established.
Finding
The cohort included 111,829 new users of short-acting beta2-agonists; 686 people had a first major adverse cardiovascular event (stroke, heart failure, myocardial infarction, arrhythmia or cardiovascular death): 359 with asthma, 239 with COPD and 88 with overlap. In asthma, short-acting beta2-agonists were not significantly associated with events against inhaled corticosteroid (HR 1.29, 95% CI 0.96 to 1.73). In COPD, short-acting beta2-agonists were associated with events against short-acting muscarinic antagonists (HR 2.02, 1.13 to 3.59), and in asthma-COPD overlap against inhaled corticosteroid (HR 2.57, 1.26 to 5.24). Mean age at cohort entry of cases was 63.8 years in asthma and 74.3 years in COPD.
Funding unknown
Lai CC, Chen CH, Wang YH, Wang CY, Wang HC. Association between overuse of short-acting β2-agonists and the risk of major adverse cardiovascular events among patients with asthma Thorax, 2026.
doi:10.1136/thorax-2024-222204 PubMed 41986159
Funding and finding
Participants
231,970
Follow-up
1 year
Funding
not read: the full text requires a subscription and is absent from PubMed Central. The Europe PMC grant list for the article names Cardinal Tien Hospital grants and 'AstraZeneca Taiwan' grant ESR-18-13978.
Finding
28,500 patients with overuse (3 or more canisters a year) and 203,470 with 0 to 2 canisters. After inverse probability of treatment weighting, 1-year major adverse cardiovascular events were 2.82 against 0.99 per 100 person-years (adjusted HR 1.25, 95% CI 1.12 to 1.39); non-fatal myocardial infarction HR 1.28 (1.09 to 1.50), ischaemic stroke 1.26 (1.08 to 1.46) and mortality 1.40 (1.24 to 1.58); haemorrhagic stroke was not significantly increased. The dose-response was non-linear, with risk peaking at 6 to 8 canisters a year.
Funding unknown
Sato K, Iwata A, Kurihara M, Mano T, Toda T. Stress cardiomyopathy (Takotsubo syndrome) in patients who received adrenergic agonist drugs: A pharmacovigilance study using the Japanese Adverse Drug Event Report (JADER) database Journal of Cardiology, 2022.
doi:10.1016/j.jjcc.2021.08.019 PubMed 34493421
Funding and finding
Funding
not read: the full text requires a subscription and is absent from PubMed Central.
Finding
Of 306 reports of Takotsubo syndrome, 58 involved adrenergic agonist drugs, 52 of them (89.7%) in women, median age in the 70s. After adjustment for age decade and sex, reporting odds ratios were significantly raised for intravenous catecholamines and for inhaled salbutamol, inhaled procaterol, transdermal tulobuterol and oral midodrine. Spontaneous reports lack denominators and do not establish incidence or causation.
Independent research
Howley MM, Papadopoulos EA, Van Bennekom CM, Van Zutphen AR, Carmichael SL, Munsie JW, et al. Asthma Medication Use and Risk of Birth Defects: National Birth Defects Prevention Study, 1997-2011 Journal of Allergy and Clinical Immunology: In Practice, 2020.
doi:10.1016/j.jaip.2020.07.033 PubMed 32745701
Funding and finding
Participants
39,375
Funding
This project was supported through Centers for Disease Control and Prevention (CDC) cooperative agreements to the Centers for Birth Defects Research and Prevention participating in the NBDPS and/or BD-STEPS.
Finding
1304 case mothers (4.6%) and 449 control mothers (4.1%) reported early-pregnancy asthma medication; albuterol was the most commonly reported bronchodilator. Bronchodilator-only use was associated with cleft palate (adjusted OR 1.50, 95% CI 1.11 to 2.02), cleft lip (1.58, 1.12 to 2.23), longitudinal limb deficiency (2.35, 1.55 to 3.54) and truncus arteriosus (2.48, 1.13 to 5.42); any bronchodilator use with cerebellar hypoplasia (2.70, 1.06 to 6.85) and tricuspid atresia (2.03, 1.06 to 3.90). Most of the 52 defects examined showed no association. Compared with bronchodilator use only in late pregnancy, early use remained associated with cleft palate, cleft lip with palate, longitudinal limb deficiency, gastroschisis and secundum atrial septal defect. Severity data were lacking, and the authors could not fully separate medication from maternal asthma.
Independent research
Garne E, Vinkel Hansen A, Morris J, Jordan S, Klungsøyr K, Engeland A, et al. Risk of congenital anomalies after exposure to asthma medication in the first trimester of pregnancy - a cohort linkage study BJOG: An International Journal of Obstetrics and Gynaecology, 2016.
doi:10.1111/1471-0528.14026 PubMed 27172856
Funding and finding
Participants
519,242
Funding
Financial support for this study was provided by the European Union under the Seventh Framework Programme (grant agreement HEALTH-F5-2011-260598). The funding source had no involvement in the study.
Finding
19,513 mothers (3.76%) had an asthma medication prescription in the exposure window; inhaled beta2-agonists were the most frequent (2.93%). For any asthma medication, the adjusted OR for a major congenital anomaly was 1.21 (99% CI 1.09 to 1.34). Short-acting beta2-agonists were associated with renal dysplasia (OR 2.37, 99% CI 1.20 to 4.67), limb reduction defects and syndactyly, at ORs of 2.00 to 2.37; the discussion states that these associations weakened and lost significance when exposure was restricted to at least two prescriptions, while the sensitivity analysis reports that the renal dysplasia association remained significant under a stricter exposure definition. Previously reported associations of inhaled beta2-agonists with cleft palate (OR 1.05, 0.44 to 2.51) and gastroschisis (1.08, 0.37 to 3.15) were not confirmed. The authors caution that many comparisons were made.
Independent research
Shakhshir LA, Karain A, Pell JP, Hastie CE, Nelson SM, Fleming M. Prenatal exposure to asthma medications and risk of neurodevelopmental disorders and educational difficulties: A systematic review and meta-analysis PLoS Medicine, 2026.
doi:10.1371/journal.pmed.1005100 PubMed 42224295
Funding and finding
Participants
3,867,170
Funding
The work is affiliated to Health Data Research UK, funded by UK public research councils and charities; the British Council funds one author's PhD. The funders had no role in design, conduct, analysis, interpretation, preparation, review or approval of the manuscript, or the decision to submit.
Finding
All included studies examined beta2-adrenergic agonists, without separating short-acting from long-acting agents. Meta-analysis of three studies (1,380,871 participants) found associations with autism spectrum disorder for exposure before conception (adjusted OR 1.34, 95% CI 1.19 to 1.52) and during pregnancy (1.29, 1.16 to 1.42), with low heterogeneity. In five studies that tried to separate medication from maternal asthma, associations in the subgroup of mothers with confirmed asthma were non-significant. An association with ADHD rests on a single study. The authors state that the evidence cannot distinguish a medication effect from confounding by indication or severity.
Textbook or database
Billington CK, Penn RB, Hall IP. β2 Agonists Handbook of Experimental Pharmacology, 2017.
doi:10.1007/164_2016_64 PubMed 27878470
Funding and finding
Funding
The authors are funded by grants HL58506 and A110007 (RBP) and MRC grant G1000861 (IPH).
Finding
Beta2 adrenoceptors are expressed on airway smooth muscle and also on airway epithelial cells, submucosal glands, vascular endothelium, vascular smooth muscle, mast cells, macrophages and eosinophils; the main adverse effects of the class, among them anxiety, tachycardia, tremor and sweating, are ascribed to cross-activation of beta1 adrenoceptors, and the accumulated evidence does not indicate anti-inflammatory effects of current therapeutic beta2 agonists. Loss of the bronchoprotective effect with chronic use has been observed in patients, consistent with receptor desensitisation in cell, tissue and mouse models. Salbutamol, the first β2-selective agonist, was synthesised in 1968 at Glaxo. Inhaled doses are 100-200 µg as required up to four times per day, with onset under 5 min, duration of effect 3-6 h and β2/β1 selectivity 27, against 63 for terbutaline, 150 for formoterol and 3000 for salmeterol. The β2 adrenoceptor was the first G-protein-coupled receptor to be cloned, has seven transmembrane domains and couples to Gs; adenylyl cyclase then catalyses formation of cAMP from ATP and cAMP activates protein kinase A, whose substrates in airway smooth muscle include myosin light chain kinase, KCa channels, heat shock protein 20, Gq-coupled receptors, Gq, phospholipase C and IP3 receptors. G-protein-coupled receptor kinases phosphorylate the receptor and promote β-arrestin binding, which uncouples it from Gs and diminishes cAMP production. Of the four coding variants of ADRB2, Arg16Gly and Gln27Glu are common, with allele frequencies between 0.3 and 0.7 and in linkage disequilibrium; Thr164Ile has an allele frequency of about 2% and alters catechol ligand binding and receptor trafficking in transfected cells; Val34Met is very rare and appears not to alter receptor function. Several studies found that frequent or regular administration of short-acting agonists impairs asthma control in Arg16Arg homozygotes, while most larger retrospective and prospective studies did not confirm these results and large genome-wide association studies of asthma identified no signal at the ADRB2 locus. Short-acting agonists are recommended on an as-required rather than a regular basis, and escalation of use should prompt review of management; widespread use of genetic profiles to dictate treatment with this drug class does not seem warranted.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute [HG002273]; Office of the Director, NIH OD [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; Biotechnology and Biological Sciences Research Council [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; State Secretariat for Education, Research and Innovation; EMBL Australia. Funding for open access charge: National Institutes of Health.
Finding
Reviewed human UniProtKB entries read on 2026-10-21 through rest.uniprot.org. ADRB1 (P08588, entry version 234): G-protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and the cAMP-dependent pathway; binds adrenaline and noradrenaline with approximately equal affinity; as part of the sympathetic nervous system it stimulates cardiomyocyte contraction; located in the cell membrane. ADCY5 (O95622, version 207): adenylate cyclase type 5, EC 4.6.1.1, catalysing ATP to 3',5'-cyclic AMP plus diphosphate with Mg2+ or Mn2+ as cofactor; activated by the G(s) alpha protein GNAS and mediating signalling downstream of ADRB1. PRKACA (P17612, version 260): cAMP-dependent protein kinase catalytic subunit alpha, EC 2.7.11.11, phosphorylating protein seryl and threonyl residues with ATP; activated by cAMP, which dissociates the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free catalytic subunits; RYR2 is among its substrates. PLN (P26678, version 222): phospholamban, expressed in heart muscle, reversibly inhibits ATP2A2/SERCA2 in the cardiac sarcoplasmic reticulum by lowering the pump's apparent affinity for Ca2+ and modulates calcium re-uptake during muscle relaxation; the inhibition is alleviated by phosphorylation, Ser16 being phosphorylated by PKA and DMPK and Thr17 by CaMK2. ATP2A2 (P16615, version 263): sarcoplasmic/endoplasmic reticulum calcium ATPase 2, EC 7.2.2.10, a magnesium-dependent pump hydrolysing ATP while translocating calcium from the cytosol into the sarcoplasmic reticulum lumen and regulating the contraction-relaxation cycle; isoforms 2 and 3 are highly expressed in the heart. RYR2 (Q92736, version 246): ryanodine receptor 2, a cytosolic calcium-activated calcium channel that releases Ca2+ from the sarcoplasmic reticulum and triggers cardiac muscle contraction, activated in cardiac myocytes by the rise in cytosolic Ca2+ that follows activation of the L-type channel CACNA1C; Ser2031 is phosphorylated by PKA and Ser2808 by CaMK2D and PKA, and the channel is identified in a complex with FKBP1B, the PKA catalytic subunit, PRKAR2A, AKAP6 and the phosphatases PP1 and PP2A. TNNI3 (P19429, version 230): cardiac troponin I, the inhibitory subunit of troponin, the thin-filament regulatory complex that confers calcium sensitivity to striated muscle actomyosin ATPase; Ser23 and Ser24 are phosphorylated by PKA and PKD/PRKD1. HCN4 (Q9Y3Q4, version 204): hyperpolarisation-activated channel permeable to Na+ and K+ with very slow activation that contributes to the native pacemaker current of the heart, If, which regulates the rhythm of the heart beat; activated by cAMP, whose binding removes a tonic inhibition conferred by the cyclic nucleotide-binding domain and leads to assembly of an active tetramer and channel opening; inhibited by extracellular Cs+; highly expressed in heart. CYP2D6 (P10635, version 245): cytochrome P450 monooxygenase that inserts one oxygen atom into a substrate and reduces the second to water with two electrons provided by NADPH through cytochrome P450 reductase, and is involved in the oxidative metabolism of drugs including antiarrhythmics and adrenoceptor antagonists.
Independent research
Pedersen TH, Clausen T, Nielsen OB. Loss of force induced by high extracellular [K+] in rat muscle: effect of temperature, lactic acid and beta2-agonist Journal of Physiology, 2003.
doi:10.1113/jphysiol.2003.041418 PubMed 12813152
Funding and finding
Funding
The study was supported by grants from the Danish Medical Research Council (no. 22-01-0189), the Danish Biomembrane Research Centre, Aarhus Universitets Forskningsfond and The Carlsberg Foundation.
Finding
In isolated rat soleus muscle exposed to 11 mM extracellular K+, tetanic force was 16 ± 4% of control at 30 °C; raising the temperature to 35 °C gave 35 ± 5%, adding 10 mM L-lactic acid 52 ± 3%, and adding 10 µM salbutamol restored force to 87 ± 2%. Together, lactic acid and salbutamol raised the IC50 for extracellular K+ from 10.7 to 13.5 mM. Force recovery produced by warming was suppressed by ouabain, and warming raised ouabain-suppressible 86Rb+ uptake by 93%, lowered intracellular Na+ by 5 mM and hyperpolarised the membrane by 5 mV, so recovery in this preparation depends on Na+-K+ pump activity. The authors ascribe the added effect of salbutamol to a higher affinity of the pump for intracellular Na+.
Independent research
Hostrup M, Jessen S, Tischer SG, Kalsen A, Hadad R, Bonde PL, et al. Lean Mass Gains, Cardiac Remodeling, and Muscle Oxidative Changes With High-Dose Salbutamol During Resistance Training: A Randomized Controlled Trial Scandinavian Journal of Medicine & Science in Sports, 2026.
doi:10.1111/sms.70302 PubMed 42274909
Funding and finding
Participants
30
Follow-up
11 weeks
Funding
The study was supported by an independent research grant from World Anti-Doping Agency (Grant 11D5VB).
Finding
Lean mass rose 1.8 kg more with salbutamol than placebo (95% CI 0.5 to 3.1). Cardiac magnetic resonance showed no between-group difference in cardiac structure or function, including left ventricular mass, whereas echocardiography showed greater posterior, septal and relative wall thickness with salbutamol (p < 0.01). Time to exhaustion in cardiopulmonary exercise testing increased 7% with placebo and not with salbutamol; muscle capillary density and citrate synthase and 3-hydroxyacyl-CoA dehydrogenase activities fell with salbutamol (p < 0.01). The dose was supratherapeutic and the participants were healthy men.
Independent research
Hostrup M, Weinreich C, Bjerre M, Kohlbrenner D, Bangsbo J, Jessen S. Inhaled salbutamol induces leanness in well-trained healthy females but not males during a period of endurance training: a randomised controlled trial ERJ Open Research, 2023.
doi:10.1183/23120541.00657-2023 PubMed 38152086
Funding and finding
Participants
40
Follow-up
6 weeks
Funding
The study was supported by Anti Doping Denmark; one author was supported by a Postdoc Mobility Fellowship of the Swiss National Science Foundation.
Finding
Salbutamol reduced fat mass in women only (-0.8 kg at 6 weeks against placebo, 95% CI -0.5 to -1.6; sex-by-treatment p = 0.048), with lean mass gain in women. Salbutamol lowered the overall rise in maximal oxygen uptake in both sexes (treatment effect p = 0.014), mainly through a blunted increase over the first 4 weeks, increases being of similar size between treatments by week 6, and lowered quadriceps strength in women by 39 N·m (17 to 61) at 6 weeks; muscle electron transport chain complex I to V abundance rose, while beta2-adrenoceptor protein content was unchanged.
Independent research
Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, et al. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease Science, 2017.
doi:10.1126/science.aaf3934 PubMed 28860381
Funding and finding
Follow-up
11 years (2004 to 2014) in the Norwegian Prescription Database
Funding
Michael J. Fox Foundation; US National Institute of Neurological Disorders and Stroke (U01 NS082157, U01NS095736, R01 NS083845); US Department of Defense; M.E.M.O. Hoffman Foundation; Prinses Beatrix Spier Fonds; American Parkinson's Disease Association; Parkinson's Disease Foundation; Branfman Family Foundation; Canadian Institutes of Health Research; Brain Canada/Krembil Foundation; Heart and Stroke Foundation of Canada; Multiple System Atrophy Coalition; Harvard NeuroDiscovery Center.
Finding
Cells: three beta2 agonists (metaproterenol, clenbuterol, salbutamol) lowered SNCA mRNA and alpha-synuclein protein in human neuroblastoma cells and rat neurons; beta2 knockout, silencing or propranolol raised them, and the effect tracked H3K27 acetylation at the SNCA promoter and enhancers. Mice: clenbuterol lowered nigral SNCA expression and protected dopaminergic neurons from MPTP. People: in Norway, salbutamol use was associated with a lower rate of Parkinson's disease (rate ratio 0.66, 95% CI 0.58 to 0.76), adjusted for sex, age and education, and propranolol with a higher rate (2.20, 1.62 to 3.00). Inhaled corticosteroid use was not associated (0.95, 0.80 to 1.12), which the authors cite against confounding by smoking.
Industry-funded
Straat ME, Hoekx CA, van Velden FHP, Pereira Arias-Bouda LM, Dumont L, Blondin DP, et al. Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue Cell Reports Medicine, 2023.
doi:10.1016/j.xcrm.2023.100942 PubMed 36812890
Funding and finding
Registration
NL9345
Participants
10
Funding
Supported by a Fonds de Recherche du Québec - Santé doctoral award, the GSK Chair in Diabetes of Université de Sherbrooke (to one author), an FRQS salary award, the Dutch Diabetes Foundation, an NWO-VENI grant, a Maria Zambrano fellowship (NextGenerationEU) and the Netherlands Cardiovascular Research Initiative with the Dutch Heart Foundation.
Finding
Salbutamol increased glucose uptake by brown adipose tissue compared with salbutamol plus propranolol, without changing glucose uptake by skeletal muscle or white adipose tissue; salbutamol-induced uptake correlated with the rise in energy expenditure. Salbutamol raised heart rate acutely by 16.9 beats/min (SD 10.5) and tended to raise energy expenditure by 7.2% (122 kcal/day, p = 0.06), whereas with propranolol energy expenditure fell 9.4%. The authors cite human biopsies and brown adipocytes in which ADRB2, not ADRB3, is the dominant adrenergic receptor.
Independent research
Szmigiel A, da Rocha MM, Browne K, Morales D, Olsen DB, Warren-Gash C, et al. Association Between β-Adrenoreceptor Agonists and Antagonists and Parkinson's Disease: Systematic Review and Meta-Analysis Pharmacoepidemiology and Drug Safety, 2025.
doi:10.1002/pds.70140 PubMed 40200766
Funding and finding
Funding
No specific funding was received for this study. Two authors are funded by Wellcome fellowships (220283/Z/20/Z and 225868/Z/22/Z); one author holds grants from NIHR, GSK and AIR@InnoHK.
Finding
Twenty of 22 studies had a high risk of bias in at least one domain; control for smoking, a protective factor for Parkinson's disease, was deficient or lacking in 12. Summary relative risk for beta2-agonists 0.93 (95% CI 0.84 to 1.03; 11 studies) and for salbutamol 0.88 (0.77 to 1.01; 7 studies); short-acting beta2-agonists 0.91 (0.88 to 0.95; 6 studies), long-acting 0.85 (0.76 to 0.96; 5 studies). Restricting to higher-quality subgroups weakened the associations or removed their significance. The funnel plot for beta2-agonists suggested publication bias (Egger p = 0.03). The authors conclude that the evidence does not support a causal association and that significant associations are most likely explained by protopathic bias and confounding; a 2018 EMA PRAC signal procedure found insufficient evidence to update product information.
Independent research
Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors Nature, 2009.
doi:10.1038/nature08144 PubMed 19458711
Funding and finding
Funding
This work was supported by the US National Institute of General Medical Sciences (grant F32 GM082028 to D.M.R. and grant RO1-GM083118 to B. K.), the Lundbeck Foundation (to S.G.F.R.), the National Institute of Neurological Disorders and Stroke (grant RO1-NS28471 to B.K.) and the Mather Charitable Foundation (to B. K.).
Finding
Review. GPCRs are the largest family of membrane proteins and mediate most cellular responses to hormones and neurotransmitters; all have seven membrane-spanning alpha-helical segments. At the human beta2 adrenoceptor, adrenaline and noradrenaline activate the stimulatory G-protein subunit Gs alpha, which stimulates adenylyl cyclase; cAMP accumulates and activates protein kinase A, and specific phosphodiesterases lower cAMP. Activated receptors are phosphorylated by G-protein-coupled receptor kinases and bind arrestin, which prevents G-protein activation and promotes internalisation.
Independent research
Walters EH, Walters JAE, Gibson PG, Jones P. Inhaled short acting beta2-agonist use in chronic asthma: regular versus as needed treatment Cochrane Database of Systematic Reviews, 2003.
doi:10.1002/14651858.CD001285 PubMed 12804401
Funding and finding
Funding
Internal sources: no sources of support supplied. External sources: Commonwealth Department of Health and Aged Care, Australia; Garfield Weston Foundation, UK.
Finding
Update of 2003 with 49 trials. Regular against as-needed use gave no clinically or statistically significant difference in airway calibre; regular use lowered rescue use by 0.80 puffs per 24 h and days with symptoms by 6.7%. The odds ratio for at least one exacerbation was 0.86 (95% CI 0.71 to 1.04; 10 parallel-group studies, n = 2922). Regular use increased direct airway reactivity, the PC20 or PD20 falling by 0.47 doubling doses (0.13 to 0.81; 4 parallel-group studies, n = 149), reduced acute bronchoprotection against direct challenge by 0.75 doubling doses (0.30 to 1.19; 3 crossover studies, n = 50) and enlarged the allergen-induced late asthmatic response by 9.96% (4.74 to 15.18; 2 crossover studies). Few studies reported adverse events: tremor odds ratio 13.47 (3.17 to 57.24), with no significant difference in headache or palpitations. In the run-out phase after withdrawal, 4 weeks in Drazen 1996 and 1 week in Ganassini 1997, no significant differences in airway calibre or responsiveness were found.
Funding unknown
Taylor DR, Town GI, Herbison GP, Boothman-Burrell D, Flannery EM, Hancox B, et al. Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol Thorax, 1998.
doi:10.1136/thx.53.9.744 PubMed 10319056
Funding and finding
Participants
165
Follow-up
three 24-week treatment periods, each followed by a 4-week washout
Funding
not read: PubMed Central holds only a scanned PDF of the article.
Finding
157 patients were analysed. Against placebo, regular salbutamol did not change morning peak flow, raised evening peak flow by 21 l/min (95% CI 17 to 26), improved only daytime symptoms, and was followed by a deteriorating asthma score over time (p < 0.01). Minor exacerbation rates were 0.88 with salbutamol and 0.97 with placebo, and major exacerbation rates 0.51 and 0.40 per patient-year; time spent in major exacerbation was longer with salbutamol (12.3 days, 95% CI 4.2 to 20.4, against 8.4 days, 5.2 to 11.6; p = 0.02). No rebound deterioration in control, lung function or bronchial hyperresponsiveness followed cessation, and no tolerance was found.
Funding unknown
Csonka LL, Vähätalo I, Ilmarinen P, Tuomisto LE, Kankaanranta H, Lehtimäki L. Regular short-acting β2-agonist use over two weeks does not increase diurnal variation or induce tolerance during home PEF monitoring Heart & Lung, 2026.
doi:10.1016/j.hrtlng.2026.102789 PubMed 41985294
Funding and finding
Participants
108
Follow-up
2 weeks of home peak expiratory flow monitoring
Funding
not read: the full text requires a subscription and is absent from PubMed Central. The Europe PMC grant list names Finnish foundations (Tampereen Tuberkuloosisäätiö, Filha, Väinö and Laina Kivi Foundation, Suomen Tuberkuloosin Vastustamisyhdistyksen Säätiö).
Finding
Mean PEF, relative and absolute diurnal variation, the number of days with significant diurnal variation, and the bronchodilator response did not differ between the week without and the week with twice-daily SABA use, in either protocol. The authors state that adverse effects of longer use cannot be ruled out.
Funding unknown
Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma Annals of Internal Medicine, 2004.
doi:10.7326/0003-4819-140-10-200405180-00010 PubMed 15148067
Funding and finding
Funding
not stated; the article lists 'Disclosures: None disclosed' and no grant support.
Finding
Against placebo, regular beta2-agonist use did not change mean FEV1 after treatment or the net FEV1 treatment effect, but reduced the peak FEV1 response to subsequent beta2-agonist by 17.8% (95% CI 8.5% to 27.2%), the FEV1 dose response by 34.8% (24% to 45.7%), the PC20 to bronchoconstrictor stimuli by 26% (11% to 37%), leukocyte beta2-receptor density by 18.3% (5.1% to 31.6%), binding affinity by 23.1% (6.8% to 39.4%) and the in vitro response to isoproterenol by 32.7% (9.0% to 56.5%).
Independent research
Ko K, Kurogi K, Davidson G, Liu MY, Sakakibara Y, Suiko M, et al. Sulfation of ractopamine and salbutamol by the human cytosolic sulfotransferases Journal of Biochemistry, 2012.
doi:10.1093/jb/mvs073 PubMed 22763752
Funding and finding
Funding
National Institutes of Health (GM085756) and a startup fund from College of Pharmacy, The University of Toledo. Conflict of interest: none declared.
Finding
HepG2 human hepatoma cells labelled with [35S]sulfate released sulfated salbutamol. Of 11 purified human cytosolic sulfotransferases, SULT1A3 was the major enzyme sulfating salbutamol. Among cytosol or S9 fractions of human lung, liver, kidney and small intestine, the small intestine showed the highest salbutamol-sulfating activity, in line with the tissue distribution of SULT1A3. Salbutamol inhibited SULT1A3-mediated dopamine sulfation, with an IC50 in line with the Km of SULT1A3 for salbutamol.
Industry-funded
Karimi L, Vijverberg SJ, Engelkes M, Hernandez-Pacheco N, Farzan N, Soares P, et al. ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta-analysis Clinical and Experimental Allergy, 2021.
doi:10.1111/cea.13965 PubMed 34128573
Funding and finding
Participants
5,903
Funding
Funding is listed per contributing study and includes industry money: PACMAN was supported by an unrestricted grant from GSK, part of a strategic alliance between GSK and the Utrecht Institute for Pharmaceutical Sciences. Other listed sources are the UK Department of Health for PASS, the Slovenian Research Agency, Singapore public research agencies, the German charity Atemwegsliga and the German Ministry of Science and Education.
Finding
Among 832 participants treated with an inhaled corticosteroid plus a long-acting beta2-agonist, the ADRB2 Arg16/Gln27 haplotype was associated with asthma exacerbations compared with Gly16/Glu27 (odds ratio 1.40, 95% CI 1.05 to 1.87) and with Gly16/Gln27 (1.43, 1.05 to 1.94), while Gly16/Gln27 against Gly16/Glu27 showed no association (0.99, 0.71 to 1.39). Among 973 participants using as-required short-acting beta2-agonists, and among those on inhaled corticosteroid monotherapy (2623) or corticosteroid with a leukotriene receptor antagonist (338), no association between the haplotypes and exacerbations was found.
Regulator
Coordination Group for Mutual Recognition and Decentralised Procedures – Human; Pharmacovigilance Risk Assessment Committee. Levosalbutamol, salbutamol: CMDh scientific conclusions and grounds for the variation, amendments to the product information and timetable for the implementation - PSUSA/00010330/202301 European Medicines Agency, PSUSA/00010330/202301, CMDh position adopted at the October 2023 meeting, 2023.
https://www.ema.europa.eu/en/documents/psusa/levosalbutamol-salbutamol-cmdh-scientific-conclusions-and-grounds-variation-amendments-product-information-and-timetable-implementation-psusa-00010330-202301_en.pdf
Funding and finding
Funding
European Medicines Agency and the EU national competent authorities
Finding
On the basis of clinical trials, large population-based observational studies and a plausible mechanism of action, PRAC considered overuse of salbutamol-containing reliever medication significant and associated with deteriorating asthma control and the risk of life-threatening exacerbations, and stated that providing patients solely with salbutamol relievers leaves the underlying inflammation untreated. New section 4.4 text: overuse of short-acting beta-agonists may mask the progression of the underlying disease and contribute to deteriorating asthma control, leading to an increased risk of severe asthma exacerbations and mortality; patients who take 'as needed' salbutamol more than twice a week, not counting use before exercise, should be re-evaluated. The benefit-risk balance was judged unchanged subject to these amendments; implementation by Member States by 25 January 2024.
Independent research
Crossingham I, Turner S, Ramakrishnan S, Fries A, Gowell M, Yasmin F, et al. Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma Cochrane Database of Systematic Reviews, 2021.
doi:10.1002/14651858.CD013518.pub2 PubMed 33945639
Funding and finding
Participants
9,657
Funding
Internal sources: National Institute for Health Research, UK (NIHR Oxford Biomedical Research Centre support for three authors; NIHR Cochrane Incentive Award NIHR130687). External sources: Wellcome Trust Career Development Fellowship 211050/Z/18/Z to one author.
Finding
Against an as-required fast-acting beta2-agonist alone, as-required budesonide-formoterol reduced exacerbations requiring systemic steroids (OR 0.45, 95% CI 0.34 to 0.60; 2 RCTs, 2997 participants, high-certainty evidence): 109 per 1000 with the beta2-agonist alone against 52 (40 to 68) per 1000. Asthma-related hospital admission or emergency or urgent care visits: OR 0.35 (0.20 to 0.60; low certainty). Differences in asthma control and spirometry were below the minimal clinically important differences, and no difference in quality of life or mortality was found. Against regular inhaled corticosteroid plus reliever: exacerbations requiring systemic steroids OR 0.79 (0.59 to 1.07; 4 RCTs, 8065 participants), 81 against 65 (49 to 86) per 1000. The two trials of the comparison with the reliever alone were SYGMA 1 (funded by AstraZeneca; terbutaline comparator) and Novel START (AstraZeneca and Health Research Council of New Zealand; salbutamol comparator); the review states that four of the trials contributing data were funded by AstraZeneca and that most were produced by a single group of investigators.
Independent research
Hatter L, Holliday M, Oldfield K, Kearns C, Barry T, Black M, et al. Budesonide-formoterol versus salbutamol as reliever therapy in children with mild asthma (CARE): a 52-week, open-label, multicentre, superiority, randomised controlled trial Lancet, 2025.
doi:10.1016/S0140-6736(25)00861-X PubMed 41033330
Funding and finding
Registration
ACTRN12620001091998
Participants
360
Follow-up
52 weeks
Funding
Health Research Council of New Zealand, Cure Kids New Zealand, and the Barbara Basham Medical Charitable Trust (managed by Perpetual Guardian).
Finding
Annualised asthma attack rates were 0.23 with budesonide-formoterol against 0.41 with salbutamol per participant per year (relative rate 0.55, 95% CI 0.35 to 0.86). At least one adverse event occurred in 162 of 179 (91%) and 167 of 181 (92%) (odds ratio 0.79, 0.35 to 1.79).
Independent research
Martinez FD, Chinchilli VM, Morgan WJ, Boehmer SJ, Lemanske RF Jr, Mauger DT, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial Lancet, 2011.
doi:10.1016/S0140-6736(10)62145-9 PubMed 21324520
Funding and finding
Registration
NCT00394329
Participants
288
Follow-up
44 weeks
Funding
The study was funded by grants from the National Heart, Lung and Blood Institute, which also established and managed the independent data and safety monitoring board. The corresponding author had full responsibility for study design, data collection, statistical analysis, interpretation and writing, and the authors had complete independence over the conduct, integrity and publication of the study.
In-kind support
TEVA Pharmaceutical Industries provided beclomethasone dipropionate-HFA and placebo.
Finding
Four arms, each with albuterol 180 µg as rescue: twice-daily beclomethasone plus beclomethasone as rescue (combined, n = 71), twice-daily beclomethasone (daily, n = 72), beclomethasone as rescue only (rescue, n = 71) and placebo, that is rescue albuterol alone (n = 74). The probability of a first exacerbation requiring oral corticosteroids by 44 weeks was 49% (95% CI 37 to 61) with rescue albuterol alone, 28% (18 to 40) with daily beclomethasone (hazard ratio 0.49, 0.28 to 0.85; Hochberg-adjusted p = 0.033), 31% (21 to 43) with combined treatment and 35% (24 to 47) with rescue beclomethasone. Treatment failure occurred in 17 of 74 (23%) with albuterol alone, 2 of 72 (2.8%) with daily beclomethasone, 4 of 71 (5.6%) with combined treatment and 6 of 71 (8.5%) with rescue beclomethasone. Children in the daily and combined arms grew 1.1 cm (SD 0.3) less than the placebo arm (p < 0.0001); growth in the rescue arm did not differ (0.3 cm, SD 0.2, p = 0.26). Albuterol use increased in all participants during the trial, without difference between treatment groups.
Independent research
Bruton A, Lee A, Yardley L, Raftery J, Arden-Close E, Kirby S, et al. Physiotherapy breathing retraining for asthma: a randomised controlled trial Lancet Respiratory Medicine, 2018.
doi:10.1016/S2213-2600(17)30474-5 PubMed 29248433
Funding and finding
Registration
ISRCTN88318003
Participants
655
Follow-up
12 months
Funding
Funding was provided by the UK National Institute of Health Research, Health Technology Assessment funding stream. The funder was not involved in the study design, data collection, data analysis, data interpretation, or in the writing of the report.
Finding
At 12 months AQLQ was higher with the DVD and booklet than usual care (adjusted mean difference 0.28, 95% CI 0.11 to 0.44) and with face-to-face retraining (0.24, 0.04 to 0.44), the two interventions being equivalent; the largest gains were in the emotion domain. FEV1 and exhaled nitric oxide did not differ. Asthma attacks occurred in 24 of 261 (9%) with the DVD, 15 of 132 (11%) face-to-face and 39 of 262 (15%) with usual care (incidence rate ratio for DVD 0.68, 0.39 to 1.20); bronchodilator prescriptions were non-significantly lower (0.83, 0.68 to 1.03). Serious adverse events: 11 (4%), 4 (3%) and 20 (8%).
Independent research
Royal College of Physicians; Levy ML, Andrews R, Buckingham R, Evans H, Francis C, Houston R, et al. Why asthma still kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry report Royal College of Physicians, London, May 2014, 2014.
https://www.rcp.ac.uk/media/i2jjkbmc/why-asthma-still-kills-full-report.pdf
Funding and finding
Participants
195
Funding
The National Review of Asthma Deaths is commissioned by the Healthcare Quality Improvement Partnership (HQIP) on behalf of NHS England, NHS Wales, the Health and Social Care Division of the Scottish Government and the Northern Ireland Department of Health, Social Services and Public Safety, and delivered by the Clinical Effectiveness and Evaluation Unit of the Royal College of Physicians.
Finding
Of 195 people who died from asthma, 189 (97%) were prescribed a short-acting beta2-agonist at the time of death; for the 165 with known numbers, a median of 10 (IQR 2 to 21, range 0 to 112) inhalers were issued in the year before death, 92 (56%) received more than six, 65 (39%) more than 12 and 6 (4%) more than 50. 168 (86%) were prescribed inhaled corticosteroid preventers, alone or in combination; of 128 with known numbers, 49 (38%) were issued fewer than four and 103 (80%) fewer than 12 preventer inhalers in the year. Of 155 whose severity could be estimated, 14 (9%) were treated as mild (BTS step 1), 76 (49%) as moderate and 61 (39%) had severe asthma. Personal asthma action plans were known to have been provided to 44 (23%); 37 (19%) were current smokers; panels found avoidable factors related to implementation of guidelines in 89 (46%) deaths.
Expert consensus
Reddel HK, FitzGerald JM, Bateman ED, Bacharier LB, Becker A, Brusselle G, et al. GINA 2019: a fundamental change in asthma management European Respiratory Journal, 2019.
doi:10.1183/13993003.01046-2019 PubMed 31249014
Funding and finding
Funding
No support statement is given. The authors are members of the GINA Science Committee or the GINA Board; the article states that GINA does not accept donations and that its work is supported only by the sale and licensing of GINA reports and other publications and by the voluntary work of committee members.
Finding
In April 2019 the Global Initiative for Asthma stopped recommending treatment of asthma in adults and adolescents with short-acting beta2-agonists alone, recommending instead symptom-driven treatment in mild asthma or daily inhaled corticosteroid-containing treatment, to reduce the risk of serious exacerbations. The stated grounds include case-control studies linking overuse of short-acting agonists to asthma death, randomised trials finding no advantage of regular over as-needed use, the finding of the UK National Review of Asthma Deaths that 9% of asthma deaths occurred in patients treated with a short-acting agonist alone and 39% were associated with excess prescriptions for such agonists, and an almost two-thirds reduction in severe exacerbations with as-needed low-dose budesonide-formoterol compared with as-needed short-acting agonist. In the SYGMA 1 trial 12% of patients receiving as-needed short-acting agonist had a severe exacerbation within 12 months. Among adults with apparently mild asthma, 30-37% of those with acute asthma, 16% of those with near-fatal asthma and 15-20% of those dying of asthma had symptoms less than weekly in the previous three months.
Expert consensus
National Institute for Health and Care Excellence; British Thoracic Society; Scottish Intercollegiate Guidelines Network. Asthma: diagnosis, monitoring and chronic asthma management (BTS, NICE, SIGN) National Institute for Health and Care Excellence, NICE guideline NG245, published 27 November 2024, 2024.
https://www.nice.org.uk/guidance/ng245/chapter/Recommendations
Funding and finding
Funding
not stated
Finding
Do not prescribe short-acting beta2 agonists to people of any age with asthma without a concomitant prescription of an inhaled corticosteroid. Offer a low-dose inhaled corticosteroid/formoterol inhaler taken as needed (anti-inflammatory reliever, AIR, therapy) to people aged 12 and over with newly diagnosed asthma, and change people with confirmed asthma who use a short-acting beta2 agonist only to as-needed AIR therapy. For children aged 5 to 11 years with newly diagnosed asthma, offer twice-daily paediatric low-dose inhaled corticosteroid with a short-acting beta2 agonist as needed. In November 2025 only certain budesonide/formoterol inhalers were licensed for as-needed AIR therapy in mild asthma, and the supporting evidence came from a dry powder inhaler.
Industry-funded
Nwaru BI, Ekström M, Hasvold P, Wiklund F, Telg G, Janson C. Overuse of short-acting β2-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme European Respiratory Journal, 2020.
doi:10.1183/13993003.01872-2019 PubMed 31949111
Funding and finding
Participants
365,324
Follow-up
average 85.4 months after a one-year baseline period
Funding
The study was sponsored by AstraZeneca. Two authors were employees of AstraZeneca and one was an employee of Statisticon, for which AstraZeneca is a client; statistical analysis was conducted by the Statisticon employee and the first author, and analysis, interpretation and drafting were conducted by the first author with an AstraZeneca employee in cooperation with the other authors.
Finding
A standard canister was defined as 150 doses and overuse as three or more canisters in the baseline year. Overuse was recorded in 30%: 76 619 patients (21.0%) collected three to five canisters, 27 065 (7.4%) six to 10 and 7140 (2%) 11 or more. Adjusted hazard ratios for exacerbation against two or fewer canisters were 1.26 (95% CI 1.24 to 1.28), 1.44 (1.41 to 1.46) and 1.77 (1.72 to 1.83). Deaths numbered 1365 of 254 500 (0.5%) with two or fewer canisters against 608 of 76 619 (0.8%), 375 of 27 065 (1.4%) and 216 of 7140 (3.0%); adjusted hazard ratios for all-cause mortality were 1.26 (1.14 to 1.39), 1.67 (1.49 to 1.87) and 2.35 (2.02 to 2.72). Asthma was recorded as the cause in 7, 4, 5 and 12 of those deaths.
Independent research
Tsao CL, Chan SY, Lee MH, Hsieh TYJ, Phipatanakul W, Ruran HB, et al. Adverse Outcomes Associated With Short-Acting Beta-Agonist Overuse in Asthma: A Systematic Review and Meta-Analysis Allergy, 2025.
doi:10.1111/all.16538 PubMed 40491263
Funding and finding
Funding
The authors received no specific funding for this work.
Finding
All-cause mortality was pooled from three studies: 2743 deaths among 130,629 people with overuse against 3534 among 300,451 controls, RR 2.04 (95% CI 1.37 to 3.04), I² 98.3%. The three were Nwaru 2020 (Sweden, SABINA, 1199 of 110,824 against 1365 of 254,500), To 2022 (Ontario, aged 65 years and over, 1255 of 8465 against 1942 of 17,736) and Molina 2023 (Spain, SABINA, 289 of 11,340 against 227 of 28,215). Acute exacerbations: 60,320 of 165,271 against 84,439 of 376,845, RR 1.93 (1.24 to 3.03). The authors list residual and unmeasured confounding by asthma control, environment and adherence, and variation in definitions and eras, as limitations, and state that randomised trials of overuse are impractical.
Funding unknown
Zhao N, Suissa S, Ernst P. Beta-agonist Use and Increased Asthma Mortality: Reality or Fiction? Archivos de Bronconeumología, 2023.
doi:10.1016/j.arbres.2022.12.006 PubMed 36609110
Funding and finding
Funding
not stated
Finding
Editorial. Recalls a Saskatchewan cohort in which asthma death rose with inhaled short-acting beta-agonist use, sharply above 1.7 canisters per month, and a later population cohort in which regular inhaled corticosteroid use substantially reduced asthma deaths, suggesting that under-use of inhaled corticosteroid was the more likely cause of the association between death and overuse. Of the SABINA Swedish cohort (hazard ratios 2.3 for all-cause and 31.7, 95% CI 11.9 to 84.7, for asthma-related mortality with 11 or more canisters), states that the association must be interpreted with caution because it is also consistent with confounding by disease severity and the analysis did not account for concurrent inhaled corticosteroid use. Notes that a non-eosinophilic subgroup responds to bronchodilators but not corticosteroids, in small studies, and concludes that the role of beta-agonist bronchodilators may need re-examination as asthma heterogeneity is characterised.
Expert consensus
Global Initiative for Asthma. 2021 Disclosure of Interest Information: GINA Board of Directors, GINA Science Committee Global Initiative for Asthma, disclosure of financial interest for 1 January to 31 December 2021, posted April 2022, 2022.
https://ginasthma.org/wp-content/uploads/2022/04/GINA-2021-Board-SC-Disclosures-ALL-2.pdf
Funding and finding
Funding
not stated
Finding
The document describes the GINA program as 'a collaboration between the scientific community and the private sector' and states that the private sector should not be involved in any aspect of developing documents, while asthma-related commercial organisations can be involved in dissemination and audit once documents are produced, including support for publications. The Board chair, L-P Boulet, declared institutional grants and consulting and lecture fees involving AstraZeneca, GlaxoSmithKline, Merck, Novartis and Sanofi-Regeneron among others; the Science Committee chair, H K Reddel, declared an AstraZeneca investigator-sponsored research grant and personal fees from AstraZeneca for advisory boards, steering committee work, independent medical education and consultancy, with GlaxoSmithKline, Novartis, Chiesi and Sanofi also listed.
Industry-funded
O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, et al. Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma New England Journal of Medicine, 2018.
doi:10.1056/NEJMoa1715274 PubMed 29768149
Funding and finding
Registration
NCT02149199
Participants
3,849
Follow-up
52 weeks
Funding
Funded by AstraZeneca; the registry names AstraZeneca as lead sponsor and responsible party.
Finding
3836 patients were analysed (1277 terbutaline, 1277 budesonide-formoterol, 1282 budesonide maintenance). Weeks with well-controlled asthma: 34.4% with as-needed budesonide-formoterol against 31.1% with terbutaline (OR 1.14, 95% CI 1.00 to 1.30) and 44.4% with budesonide maintenance (OR 0.64, 0.57 to 0.73). Annual severe exacerbation rates were 0.20 with terbutaline, 0.07 with as-needed budesonide-formoterol and 0.09 with budesonide maintenance (rate ratio 0.36, 0.27 to 0.49, against terbutaline). Adherence to maintenance budesonide was 78.9%; median metered inhaled glucocorticoid dose with as-needed budesonide-formoterol was 57 µg/day, 17% of the 340 µg/day with maintenance.

Updated 2026-10-22