Cataracts: Unforeseen Complication of Inhaled Corticosteroids Roshni Aggarwal, M4 University of Michigan Medical School

Inhaled Corticosteroids (ICS) Standard-of-care controller medication for asthma Also widely used in treatment of COPD Blocks multiple inflammatory pathways involved in the pathogenesis of asthma Currently available ICS include: - beclomethasone dipropionate - budesonide - fluticasone propionate - mometasone furoate - triamcinolone acetonide

Indications for ICS in Asthmatics Based on stepwise approach to management of asthma ICS is first-line treatment for asthma in most stages Stage Daily Medications Required to Maintain Long-term Control (preferred treatment only) STEP 1 Mild intermittent No daily medications needed *ICS recommended for acute exacerbations STEP 2 Mild persistent Low-dose ICS STEP 3 Moderate persistent Medium-dose ICS and long-acting β2 agonist STEP 4 Severe persistent High-dose ICS and long-acting β2 agonist (and if needed, corticosteroid tablet or syrup long-term) National Asthma Education and Prevention Program Expert Panel Report Guidelines for the Diagnosis and Management of Asthma- Update 2002

Inhalation as a Novel Drug Delivery Method Inhalation permits delivery of steroid in high concentration to target sites in lung and minimizes amount of drug reaching systemic circulation Initially physicians hypothesized that this form of drug delivery might entirely eliminate systemic side effects of ICS However, this has not been confirmed by clinical trials or experience

Mechanism of ICS Entry into Systemic Circulation All types of ICS have the potential to cause systemic side effects ICS vary in terms of oral bioavailability, % drug deposition in lung, % first-pass hepatic inactivation etc. (factors that influence amount of drug reaching systemic circulation) Rossi et al. Pulm Pharm & Therap 2007;20:23-35

Possible Systemic Side Effects of ICS Based on known systemic side effects of oral corticosteroids: HPA-axis suppression Decrease in growth velocity and leg growth in children Decrease in bone mineral density Bone fractures Osteoporosis Skin thinning and bruising Glaucoma Cataracts

Link Between Corticosteroids and Cataracts Use of systemic corticosteroids is established risk factor for development of posterior subcapsular cataracts (PSC) - prevalence of PSC 0-54% (mean 9%) based on meta-analysis by Gallant et al. (1986) of 9 studies involving 343 asthmatics treated with oral corticosteroids Case report by Kewley (1980) first suggested that ICS may also lead to development of cataracts - case reports often confounded by previous exposure of asthmatic patients to oral corticosteroids

So do we have the answers to these questions… What is the risk of cataract development secondary to ICS? What is the effect of dose and/or duration of ICS use? How does this risk vary with age? How do ICS compare with oral corticosteroids in terms of risk of cataract? Let’s look at the results of four retrospective studies…

1 - The Blue Mountains Eye Study Community-based cross-sectional study in Blue Mountains, Australia Recruited 3,654 people (49-97 years old) Questionnaire used to collect information regarding steroid use, including: - current or prior use of ICS, including puffs per week and duration - current or prior use of corticosteroids, including dosage and duration Ophthalmologic exams performed on each patient to record presence, type, and severity of cataracts Cumming et al. Use of inhaled corticosteroids and the risk of cataracts. NEJM 1997;337(1):8-14.

BMES Patient Population Of 3,313 subjects who provided information about corticosteroid use: 370 subjects used ICS alone or in combination with oral steroids (164 currently, 206 previously) Subjects matched with regards to other potential risk factors for cataracts (age, sex, DM, HTN, smoking history, sun damage)

Increased Prevalence of Cataracts Among ICS Users 1. Relative Prevalence of Cataracts Secondary to ICS Use (past and present)* Type of cataract Relative prevalence 95% CI Posterior subcapsular 1.9 1.3-2.8 Nuclear 1.5 1.2-1.9 Cortical 1.1 0.9-1.3 2. Relative Prevalence of Cataracts Secondary to Current ICS Use Only* Type of cataract Relative prevalence 95% CI Posterior subcapsular 2.6 1.7-4.0 Nuclear 1.5 1.1-2.0 Cortical 1.4 1.1-1.7 * All trends remained the same when subjects with current or prior use of systemic corticosteroids were removed from the analysis. Relative prevalence of PSC secondary to current ICS use increased to 3.2 (95% CI 1.7-6.1) in that model.

Dose-Response Relation Between Beclomethasone and Cataracts 3. Relative Prevalence of PSC With Increasing Weekly Beclomethasone Dose Weekly dose of beclomethasone (among all users) Relative prevalence PSC (p<0.001 for trend) 95% CI ≤14 puffs 1.3 0.6-2.8 15-28 puffs 2.1 1.1-3.9 >28 puffs 3.1 1.7-5.7 4. Relative Prevalence of PSC With Increasing Lifetime Beclomethasone Dose* Lifetime dose of beclomethasone (current users only) Relative prevalence PSC (p<0.001 for trend) 95% CI <1000 mg 2.5 1.1-5.8 1000-1999 mg 5.4 2.0-14.7 ≥ 2000 mg 5.5 2.3-13.0 * This dose-response relation became less evident (p=0.06) in the model restricted to subjects with no current or prior use of systemic corticosteroids.

Key Findings of Blue Mountain Eye Study ICS use associated with increased prevalence of PSC and nuclear cataracts (even after controlling for the use of systemic corticosteroids) Results consistent with known relation between use of systemic corticosteroids and presence of PSC Possible dose-response relation between beclomethasone and PSC (though may have been influenced by confounding use of systemic corticosteroids)

2 - The RAMQ Database Study Case-control study Utilized Quebec’s universal health insurance plan database (RAMQ) Enrolled 3,677 patients ≥70 years old with cataract extraction between 1992 and 1994 Randomly selected 21,868 controls from patients without diagnosis of cataract and matched them to cases Excluded patients with systemic steroid treatment Adjusted for age, sex, DM, HTN, glaucoma, ophthalmic steroids, and # physician claims for services Garbe et al. Association of inhaled corticosteroid use with cataract extraction in elderly patients. JAMA 1998;280(6):539-543.

Increased Risk of Cataracts with Prolonged ICS Use Odds Ratio of Cataract Extraction According to Cumulative Treatment Duration with ICS (excluding patients with oral steroid use) Cumulative Treatment Duration Adjusted Odds Ratio (95% CI) No treatment 1.00 Up to 1 year 0.90 (0.76-1.06) 1-3 years 0.98 (0.64-1.50) >3 years 3.06 (1.53-6.13)

Increased Risk of Cataracts with Long-Term High Dose ICS Odds Ratio of Cataract Extraction According to Average Daily Dose of ICS Stratified by Cumulative Duration of ICS Use* Dose of ICS Adjusted Odd Ratio (95% CI) No treatment 1.00 Cumulative Treatment Duration with ICS for ≤ 1 Year Low to medium dose 0.94 (0.76-1.16) High dose 0.86 (0.65-1.12) Cumulative Treatment Duration with ICS for 1-2 Years Low to medium dose 0.79 (0.41-1.52) High dose 0.85 (0.35-2.08) Cumulative Treatment Duration with ICS for >2 Years Low to medium dose 1.63 (0.85-3.13) High dose 3.40 (1.49-7.76) Excluding patients with use of oral steroids, flunisolide, or triamcinolone. Low to medium dose, average daily dose of up to 1mg beclomethasone or budesonide. High dose, average daily dose of more than 1 mg beclomethasone or budesonide.

Risk of Cataracts with Oral Corticosteroids Odds Ratio of Cataract Extraction According to Cumulative Treatment Duration with Oral Corticosteroids Cumulative Treatment Duration Adjusted Odds Ratio (95% CI) No treatment 1.00 Up to 1 year 0.97 (0.85-1.12) 1-3 years 1.98 (1.44-2.71) >3 years 2.33 (1.61-3.38)

Key Findings of RAMQ Database Study ICS use associated with 3-fold increased risk of cataracts in the elderly population after 3 years of cumulative treatment High daily dose beclomethasone or flunisolide with cumulative treatment duration >2 years associated with increased risk of cataracts Oral corticosteroid use associated with increased risk of cataracts after only 1 year of cumulative treatment (compared to 3 years for ICS) Based on 1.75% baseline incidence of cataract extraction in study population, prolonged use of ICS will give rise to 361 additional cases of cataract extraction per 10,000 elderly persons per year

3 – The United Kingdom GPRD Study #1 Retrospective observational cohort study with nested case-control analysis Utilized United Kingdom-based General Practice Research Database Selected total 201,816 patients (3-90 years old) Observational cohort study compared ICS users to non-users, all of whom had a diagnosis of asthma or COPD (103,289 ICS users vs. 98,257 non-users) Nested case-control analysis compared patients with diagnosis of cataracts to control patients without a diagnosis of cataracts from the base cohort of non-users and ICS-users (1,194 cases vs. 2,387 matched controls) Jick et al. The risk of cataract among users of inhaled steroids. Epidemiology 2001;12(2):229-234.

Risk of Cataracts with ICS vs. Systemic Steroids Steroid Exposure Adjusted Relative Risk Estimate* 95% CI Non-Exposed+ (Asthmatics only) 1.0 ICS Use Only 1.3 1.1-1.5 Oral Steroid Use Only (Asthmatics only) 2.0 1.7-2.2 * Each relative risk estimate is adjusted for age and sex. + Reference group.

Risk of Cataracts with Increasing ICS Use in All Age Groups Jick et al. Epidemiology 2001;12(2):229-234.

Risk of Cataracts with Increasing ICS Use Stratified by Age No. Prescriptions Filled Relative Risk Estimate 95% CI Age <40 1 prescription 2-9 10-19 ≥20 2.7 1.0 16 0.4 0.8-9.8 0.4-2.8 0.2-12.2 0.05-3.9 Age 40-60 1.4 0.8 1.7 0.8-2.4 0.7-1.5 0.4-1.6 1.1-2.8 Age ≥70 0.9 1.3 1.5 1.8 0.6-1.3 1.0-1.6 1.1-2.2 1.4-2.3

Key Findings of United Kingdom GPRD Study #1 Age modifies association between ICS use and risk of cataract with the greatest effect among the oldest patients at the highest dosages of ICS possible differential effect of ICS at different ages or diagnostic bias/uncontrolled confounders among older patients (e.g. asthma severity, age-related exposure) No apparent increase in risk of cataracts with ICS use in children and young adults - suggests that results of previous related studies conducted in older patients may not be applicable to all age groups

4 – The United Kingdom GPRD Study #2 Population-based case-control study Utilized newer version of General Practice Research Database in UK Selected 15,749 patients with cataract and 15,479 patients without cataracts (cases and controls matched for age, sex, practice, and observation period) Mean age 75 years old (SD 10.0) Adjusted for systemic corticosteroid exposure and consultation rate Smeeth et al. A population based case-control study of cataract and inhaled corticosteroids. Br J Ophthalmol 2003;87(10):1247-1251.

Systemic Steroid Use and Consultation Rate as Confounders Crude odds ratio for association between any recorded exposure to ICS and cataract: 1.58 (95% CI 1.46-1.71) After adjusting for systemic steroid exposure and consultation rate,* odds ratio for association between any ICS use and cataract was reduced: 1.10 (95% CI 1.00-1.20) * UK GPRD Study #1 by Jicks et al. did not control for consultation rate in UK health system. ICS Use Odds Ratio (95% CI) p Value Never Ever Current Past Only Baseline 1.10 (1.00-1.20) 1.15 (1.03-1.27) 0.98 (0.84-1.14) 0.049 0.01 0.8

Risk of Cataract with Increasing ICS Use Level of ICS Use Odds Ratio (95% CI) P Value Daily Dose None Low (up to 400 μg) Moderate (401-800 μg) High (801-1600 μg) Very high (>1600 μg) Baseline 0.99 (0.87-1.13) 1.18 (1.00-1.39) 1.18 (0.99-1.42) 1.69 (1.17-2.43) 0.002 (for trend) Number of Prescriptions 1-9 10-19 20-29 30-39 ≥ 40 1.03 (0.91-1.16) 1.07 (0.90-1.27) 1.22 (0.96-1.55) 1.23 (0.93-1.62) 1.28 (1.01-1.61) 0.004 (for trend)

Comparisons Between the United Kingdom GPRD Studies Smeeth et al. (study #2): Selected larger case and control populations Based study on newer version of United Kingdom GPRD Controlled for not only systemic steroid exposure but also consultation rate, another important confounder based on the results of this study Showed evidence of dose-response relation and gradient with increasing duration of ICS use similar to study #1 by Jick et al. Did not investigate association between ICS use and cataracts in younger age populations unlike study #1 by Jick et al.

Meta-Analysis of Four Retrospective Studies Analysis included studies by Cumming et al., Garbe et al., Jick et al., and Smeeth et al. (all 4 discussed earlier) Approximately 20,000 cases and 50,000 controls Uboweja et al. Effect of inhaled corticosteroids on risk of development of cataract: a meta-analysis. Fund & Clin Pharm 2006;20:305-309.

Results of Meta-Analysis Pooled OR 1.48 (95% CI 1.30-1.68) Funnel Plot Uboweja et al. Fund & Clin Pharm 2006;20:305-309.

Key Conclusions from Meta-Analysis ICS associated with increased risk of cataract independent of exposure to other types of corticosteroids Number needed to harm (NNH) = 16 (95% CI 13-19) given large number of patients who receive ICS, total # of patients at risk of developing cataract quite insignificant Negative heterogeneity test assures no real differences between 4 pooled studies Funnel plot shows asymmetric distribution of studies; cannot rule out publication bias Still need 9 negative studies to make results of meta-analysis insignificant

Further Considerations Risk of increased cataract with ICS use needs to be weighted against benefits of ICS for managing symptoms of asthma and COPD Need placebo-controlled prospective trials to fully evaluate relation-ship between ICS use and cataract development - difficult given large time interval required between exposure and effect Further evaluation required to clarify causal association between dosage and duration of drug use

Ciclesonide What’s on the Horizon for Safe and Effective ICS Use? Manipulation of physiochemical properties of ICS in order to: optimize pharmacodynamic and pharmacokinetic properties produce an agent that effectively controls asthma with minimal local and systemic side effects Development of new-generation ICS Ciclesonide

Ciclesonide: A Non-Halogenated ICS Parent compound with almost no binding affinity to gluco-corticoid receptor Cleaved by endogenous esterases in airway to form active metabolite, des-CIC des-CIC lipophilic and readily conjugates to fatty acids at C-21 OH Results in increased uptake of drug into target cells Acts as low-release reservoir from which drug gradually becomes available after hydrolysis by intracellular lipases Rossi et al. Pulm Pharm & Therap 2007;20:23-35.

Favorable Physiochemical Properties of Ciclesonide High efficacy small particle size (<2 μm) results in high lung deposition and penetration Favorable tolerability - oropharyngeal deposition of des-CIC >1 order of magnitude lower than that of budesonide when administered by MDI at same dose low risk of oral side effects such as candidiasis and hoarseness Low risk of systemic side effects - oral bioavailability of ciclesonide and its active metabolite <1% - high degree of serum protein binding (99%) - high first-pass hepatic extraction - rapid metabolism and clearance (ciclesonide t1/2 0.94 h, des-CIC t1/2 2.79 h)

Data on efficacy Data on safety Clinical Trials To-Date Support Efficacy and Safety of Ciclesonide Data on efficacy provides lung function control superior to that of placebo and comparable with that of budesonide and fluticasone FEV1 significantly improved in asthmatics who switched to ciclesonide while it significantly decreased in asthmatics who switched to placebo Data on safety safety of ciclesonide at various dosages was evaluated in through two identical, multi-center, double-blind, placebo-controlled studies in 1031 children rate of systemic adverse events low and comparable in all treatment groups serum and 24-h urine cortisol levels similar to placebo with no effect on HPA axis

Conclusions ICS therapy is first-line treatment for asthma of most severities and is also widely used in treatment of COPD Retrospective studies show evidence of increased risk of cataract with ICS use, particularly in elderly patients who receive prolonged high-dose ICS therapy Goal is to minimize long-term systemic ICS burden with lowest possible maintenance dose for optimal control of asthma and improved quality of life Newer generation ICS, such as ciclesonide, can be designed with improved pharmokinetic and pharmacodynamic properties that result in enhanced efficacy and reduced systemic side effects

References Cumming et al. Use of inhaled corticosteroids and the risk of cataracts. NEJM 1997;337(1):8-14. Gallant et al. Oral glucocorticoids and their complications: A review. J Am Acad Dermatol 1986;14(2):161-77 Garbe et al. Association of inhaled corticosteroid use with cataract extraction in elderly patients. JAMA 1998;280(6):539-543. Jick et al. The risk of cataract among users of inhaled steroids. Epidemiology 2001;12(2):229-234. Kewley GD. Possible association between beclomethasone dipropionate aerosol and cataracts. Aust Paediatr J 1980;16:117-118. Lipworth BJ. Systemic adverse effects of inhaled corticosteroids therapy. Arch Intern Med 1999;159(9):941-955. National Asthma Education and Prevention Program Expert Panel Report Guidelines for the Diagnosis and Management of Asthma- Update on Selected Topics 2002 (NIH Publication No. 97-4051). Rossi et al. Safety of inhaled corticosteroids: Room for improvement. Pulm Pharm & Therap 2007;20:23-35. Smeeth et al. A population based case-control study of cataract and inhaled corticosteroids. Br J Ophthalmol 2003;87(10):1247-1251. Uboweja et al. Effect of inhaled corticosteroids on risk of development of cataract: a meta-analysis. Fund & Clin Pharm 2006;20:305-309.