Impact of inhaled and intranasal corticosteroids on glucose metabolism and diabetes mellitus: A mini review

Table 1 Studies showing no worsening of glucose metabolism/diabetes mellitus by inhaled corticosteroid/intranasal corticosteroid

Ref.	Study design	Patient population	ICS or INS exposure	Outcomes reported
Blackburn et al[18], 2002	Population-based cohort study	38441 elderly (≥ 66 years old) ICS users versus 53845 non-ICS users	Types and doses of ICS not stated	Over 3 yr, no association of ICS with incident DM
Borsi et al[36], 2018	Non-randomized trial	35 non-diabetic adults with mild to moderate asthma	BUD ICS 320 mcg every 12 h	Over 2 mo, ICS had no effect on HbA1c, insulin level and insulin sensitivity (HOMA-IR)
Canis et al[37], 2007	Non-randomized trial	Non-diabetic adults (12 asthma, 6 COPD)	BUD ICS 400 mcg twice daily	Over 8 wk, ICS had no effect on glucose, insulin level and insulin sensitivity (HOMA-IR)
Dendukuri et al[38], 2002	Nested case-control study	Adults aged ≥ 65 yr. 1494 cases of incident DM versus 14931 controls	Various types and doses of ICS	No increased risk of incident DM
Ebden et al[39], 1989	Prospective observational study	14 normal and 24 diet controlled DM subjects	BDP 2000 mcg/d for 2 wk	Over 2 wk, ICS did not worsen glucose tolerance test results or insulin levels
Faul et al[40], 2009	Crossover RCT	12 DM patients with asthma or COPD	FP ICS 440 mcg twice daily versus no ICS	Over 6 wk, no difference in HbA1c
Flynn et al[41], 2014	Record linkage study	4305 patients with COPD in Scotland	Various types and doses of ICS	Over at least 2 yr of follow-up, ICS did not increase incident DM or worsen pre-existing DM control
Giep et al[42], 1996	RCT	19 ventilator-dependent neonates < 1500 g birthweight	BDP ICS 1 mg/kg/d via ventilator circuit	No effect on blood glucose
Kiviranta and Turpeinen[20], 1993	Prospective observational study	15 adults with uncontrolled asthma; 15 healthy controls	Up to 2000 mcg/d of BDP ICS, and up to 1600 mcg/d of BUD ICS	Over 8 mo, no change of fasting glucose and insulin
Lee et al[33], 2016	Nested case-control study using South Korean claims database	Pregnant women who delivered between 1 January 2009 and 31 December 2011. 34190 GDM cases and 170934 control subjects	Various types and doses of ICS	ICS use was not associated with increase in the risk of GDM
Lempp et al[43], 2022	Electronic medical records study	127 patients aged 18 to 80 with COPD and type 2 DM on at least 2 oral anti-glycemic medications from 1 January 2000 to 31 December 2017	ICS (64 patients) versus no ICS (63 patients). Various types and doses of ICS	Over 5 yr, no difference in rate of DM worsening to HbA1c > 10% (threshold chosen as add-on insulin would be considered)
O’Byrne et al[21], 2012	Pooled analyses of RCTs	44528 patients with asthma (60 trials) or COPD (8 trials)	BUD and fluticasone ICS at various doses	Over a mean follow-up of 210 d in asthma trials and 268 d in COPD trials, no association between ICS use and hyperglycemia or incident DM
Pauwels et al[19], 1999	RCT	1277 adults with COPD and continued smoking	BUD ICS 400 mcg/d for 3 yr versus placebo	No increase in incident DM by BUD ICS 400 mcg/d
Pu et al[44], 2021	Systematic review of 17 RCTs which reported glucose/DM data	43430 adults with COPD	Various types and doses of ICS	No difference in glucose level, DM control or incident DM between the ICS group and the control group with follow-up ranging from 12-96 wk
Rogala et al[45], 2020	Cross-sectional study	6763 adult patients with asthma and/or diabetes	Various types and doses of ICS	No association with increased fasting glucose
Rogliani et al[46], 2014	Cross-sectional study	493 outpatients with COPD, seen between 2010-2012	Types and doses of ICS not stated	No association between ICS use and DM diagnosis
Rahman et al[47], 2021	RCT	70 patients with asthma, but no DM	Fluticasone ICS (at low to high doses) versus no ICS	Over 3 mo, no difference in fasting plasma glucose, 2 h after 75 g oral glucose intake, and in HbA1c
Slatore et al[48], 2009	Prospective cohort study	1698 adults with COPD	Various types and doses of ICS	No change of serum glucose in subjects without diabetes
Turpeinen et al[49], 1991	Prospective observational study	9 children with asthma	400-800 mcg/m2/d of BUD ICS	Over 5 mo, no change of fasting glucose and insulin
Yucel et al[50], 2009	Case-control study	141 children with asthma (cases), 52 children without asthma (controls). All children did not have DM	75% of children were using on BUD ICS, and 25% of children were using FP ICS, at various doses	No significant association between cumulative dose of ICS and HbA1c

BDP: Beclomethasone dipropionate; BUD: Budesonide; CI: Confidence interval; COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; FP: Fluticasone propionate; GDM: Gestational diabetes mellitus; HbA1c: Glycated hemoglobin; HOMA-IR: Homeostatic Model Assessment-Insulin Resistance; ICS: Inhaled corticosteroid; INS: Intranasal corticosteroid; RCT: Randomized controlled trial.

Table 2 Studies showing worsening of glucose metabolism/diabetes mellitus by inhaled corticosteroid/intranasal corticosteroid

Ref.	Study design	Patient population	ICS or INS exposure	Outcomes reported
Ajmera et al[22], 2017	Retrospective study of Medicaid claims (2005-2008)	15287 adults with newly diagnosed COPD, who were diabetes free at baseline	Types and doses of ICS not stated	Over 1 yr, ICS use associated with greater risk of new-onset diabetes (adjusted OR = 1.23, 95%CI: 1.07-1.47)
Ben-Dov et al[17], 2023	Case report	9-mo-old female with type 1 DM	Off-label use of otic ciprofloxacin 0.3%/dexamethasone 0.1% drops in the nasal passage for choanal obstruction with granulation tissue	Over 7 d, average daily blood glucose increased by 86 mg/dL. Hyper-glycemic spikes resolved within 2 d after switching to mometasone furoate 0.05% spray
Faul et al[51], 1998	Case report	67-year-old asthmatic man	FP ICS 2000 mcg/d	Over 40 wk, patient developed glycosuria with rise of HbA1c to 8.2%. Glycosuria resolved and HbA1c fell to 7.0% with reduction of FP ICS to 500 mcg/d
Faul et al[52], 1999	Case report	67-year-old asthmatic man	BUD ICS 2000 mcg/d	Over 20 wk, patient developed glycosuria with rise of HbA1c to 8.2%. Glycosuria resolved and HbA1c fell to 7.2% with reduction of BUD ICS to 800 mcg/d
Gayle et al[23], 2019	Nested case-control study	220971 adults with COPD and previous smoking registered at a United Kingdom Clinical Practice Research Datalink practice (January 2010-December 2016)	Types and doses of ICS not stated	Increased incident DM (OR = 1.73, 95%CI: 1.65-1.82), adjusted for smoking status, deprivation, BMI, hypertension, coronary heart disease and heart failure
Kruszynska et al[53], 1987	Prospective observational study	9 normal adults aged 21-44 yr	BDP ICS 500 mcg twice daily	Over 4 wk, ICS use associated with increased peak blood glucose (7.1 versus 6.7 mmol/L, P < 0.01) after 75 g oral glucose load. No effect on fasting blood glucose or HbA1c
Lelii et al[54], 2016	Case report	2-year-old boy with recurrent wheezing	FP ICS 100 mcg twice daily for 2 mo before presentation with whining, agitation, and diuresis	Transient symptomatic hyperglycemia (10 mmol/L). FP ICS then replaced with montelukast
Lund et al[24], 2023	Case-only symmetry analysis of Danish national registries	348996 individuals > 40 yr with a first-ever prescription for any antidiabetic drug 1996-2018	Inhaled β2-agonists combined with glucocorticoids	Increased risk of incident diabetes (SR = 1.35, 95%CI: 1.28-1.42 and SR = 1.14, 95%CI: 1.06-1.22 in replicate analyses)
Metsälä et al[25], 2020	Nationwide, register-based case-cohort study	Children who were born January 1, 1995, through December 31, 2008, in Finland and diagnosed with type 1 DM by 2010 (n = 3342), compared with 10% random sample from each birth-year cohort (n = 80909)	Beclomethasone, BUD, fluticasone. Dose not stated	Over a median of 7.9 yr, increased risk of type 1 DM after adjusting for other anti-asthmatic drugs, asthma, sex, and birth decade (HR = 1.29, 95%CI: 1.09-1.52), if patients received high-dose ICS (> 800 mcg budesonide equivalent dose)
Mizrachi et al[16], 2012	Retrospective observational study	1768 DM patients treated with INS, with 245 patients providing HbA1c data and 163 patients providing fasting glucose data	BUD, FP, triamcinolone acetonide INS. Dose not stated	Over 3 mo, triamcinolone acetonide associated with increased fasting glucose but not with HbA1c. Other INS had no association with either glucose or HbA1c changes
Price et al[28], 2016	Matched cohort study	682 adults (≥ 40 years old) with COPD prescribed ICS in two large United Kingdom databases (1983-2016)	Types and doses of ICS not stated	Over 12-18 mo of follow-up, ICS prescription associated with increased HbA1c, with adjusted difference 0.16% (95%CI: 0.05%-0.27%) in all COPD patients, and 0.25% (95%CI: 0.10%-0.40%) in mild-to-moderate COPD patients. ICS prescription also associated with more diabetes-related general practice visits and more frequent glucose strip prescriptions. Associations were stronger for higher cumulative ICS doses (> 250 mg FP equivalent), compared to ≤ 125 mg
Price et al[26], 2019	Matched cohort study	18774 adults (≥ 40 years old) with COPD initiating ICS or long-acting bronchodilator in two large United Kingdom databases (1983-2016)	Types and doses of ICS not stated	Over a median follow-up at least 3.5 yr, ICS use associated with increased risk of incident DM (HR = 1.27, 95%CI: 1.07-1.50). ICS use also worsened DM control for high-dose ICS (mean daily dose ≥ 500 mcg FP equivalent)
Saeed et al[55], 2020	Cohort study using Danish health databases	50148 adults with COPD	Predominantly BUD (about 50%) and fluticasone (about 45%) ICS, at various doses. Other ICS (< 5%) used included beclomethasone, ciclesonide and mometasone	Over 7 yr, ICS use was associated with an increased risk of DM (HR = 1.16, 95%CI: 1.01-1.32) for high-dose ICS use (≥ 970 mcg BUD equivalent) and BMI < 30 kg/m2
Schou and Wolthers[15], 2011	Crossover RCT	17 children with asthma	BUD ICS 400 mcg daily for 1 wk	Over 1 wk, ICS use increased serum fructosamine compared to no ICS use (228.1 μmol/L versus 223.1 μmol/L, P = 0.02)
Slatore et al[48], 2009	Prospective cohort study	1698 adults with COPD, among United States veterans enrolled in 7 primary care clinics between February 1997 and December 1999	Various types (e.g., beclomethasone, flunisolide, fluticasone) and doses of ICS	Over 2-4 yr, among diabetics only, there was a 1.82 mg/dL (95%CI: 0.49-3.15) increase in serum glucose, for every 100-mcg triamcinolone equivalent/d increase in ICS dose
Ställberg et al[29], 2020	Cohort study	7078 Swedish patients with COPD using data from real-world, primary care settings	Types and doses of ICS not stated	Over at least 6 mo, ICS use, especially at high dose (≥ 640 mcg/d BUD equivalent), was associated with incident type 2 DM
Suissa et al[27], 2010	Nested case-controlled study using a Canadian health insurance database	388584 patients with respiratory disease	Various types of ICS (beclomethasone, BUD, triamcinolone, fluticasone, flunisolide), at various doses	Over 5.5 yr of follow-up, 34% increased rate of initiation of an anti-diabetic agent, especially in patients receiving high dose ICS (≥ 1000 mcg/d FP equivalent). In diabetics on oral hypoglycemic agents, ICS use increased risk of progression to insulin

BMI: Body-mass index; BUD: Budesonide; CI: Confidence interval; COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; OR: Odds ratio; FP: Fluticasone propionate; HR: Hazard ratio; ICS: Inhaled corticosteroid; INS: Intranasal corticosteroid; RCT: Randomized controlled trial; SR: Sequence ratio.

Table 3 Methods to reduce the impact of inhaled corticosteroid and intranasal corticosteroid on glucose metabolism and diabetes mellitus

Strategy	Methods
Minimize ICS doses	Use non-pharmacological measures (e.g., trigger avoidance, smoking cessation, vaccination to avoid respiratory infections) to optimize disease control and reduce the need for high dose ICS[2]
	Manage comorbid conditions to optimize disease control (e.g., management of obesity, OSA, heart failure, anxiety, depression) and reduce the need for high dose ICS. Consider using the “treatable traits” approach for holistic management of chronic respiratory diseases[30]
	Use long-acting bronchodilators to reduce the need for high dose ICS[2]
	Ensure good inhaler technique (or use valved holding chamber) to improve lung delivery and effectiveness of ICS, reducing the need for high dose ICS[2]
	Consider intermittent formoterol-ICS therapy rather than regular ICS for asthma[31]
	Actively step-down regular ICS dosing, including changing regular to intermittent ICS use, by clinical assessment[31]
	Actively step-down regular ICS dosing by measuring FENO in asthma[32]
	Actively step-down or step-off ICS if peripheral eosinophil count < 300/μL in well-controlled COPD[2]
Minimize INS doses	Use non-pharmacological measures (e.g., trigger avoidance, smoking cessation, vaccination to avoid respiratory infections) to optimize disease control and reduce the need for high dose INS[56]
	Use non-steroidal medications like intranasal antihistamines to reduce the need for high dose INS[56]
	Ensure good intranasal delivery technique to improve effectiveness of INS, reducing the need for high dose INS
	Actively step-down regular INS dosing, including changing regular to intermittent INS use, following clinical assessment, e.g., as-needed intranasal corticosteroids for seasonal allergic rhinitis[57]
Maintain hepatic inactivation of ICS and INS	Avoid strong CYP450 3A4 inhibitors like clarithromycin, itraconazole, ketoconazole, and voriconazole[3,9]
Minimize risk of hyperglycemia	Avoid long-term oral corticosteroids[18]
	Weight management for overweight and obese patients[58]
	Ensure good glycemic control for diabetic patients[58]

COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; FENO: Fractional exhaled nitric oxide; ICS: Inhaled corticosteroid; INS: Intranasal corticosteroid; OSA: Obstructive sleep apnea.