cataracts: unforeseen complication of inhaled corticosteroids

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

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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 - PowerPoint PPT Presentation

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Page 1: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

Cataracts: Unforeseen Complication of Inhaled

Corticosteroids

Roshni Aggarwal, M4University of Michigan Medical

School

Page 2: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Page 3: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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 1Mild intermittent

No daily medications needed*ICS recommended for acute exacerbations

STEP 2Mild persistent

Low-dose ICS

STEP 3Moderate persistent

Medium-dose ICS and long-acting β2 agonist

STEP 4Severe 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

Page 4: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Page 5: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

Mechanism of ICS Entry into Systemic Circulation

Rossi et al. Pulm Pharm & Therap 2007;20:23-35

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)

Page 6: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Page 7: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Page 8: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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?

So do we have the answers to these questions…

Let’s look at the results of four retrospective studies…

Page 9: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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 cataractsCumming et al. Use of inhaled corticosteroids and the risk of cataracts. NEJM 1997;337(1):8-14.

Page 10: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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)

Page 11: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

Increased Prevalence of Cataracts Among ICS Users

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

1. Relative Prevalence of Cataracts Secondary to ICS Use (past and present)*

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.

Page 12: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

3. Relative Prevalence of PSC With Increasing Weekly Beclomethasone Dose

Dose-Response Relation Between Beclomethasone and Cataracts

* 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.

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

4. Relative Prevalence of PSC With Increasing Lifetime Beclomethasone Dose*

Page 13: Cataracts: Unforeseen Complication of Inhaled 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)

Page 14: Cataracts: Unforeseen Complication of Inhaled 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.

Page 15: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

Increased Risk of Cataracts with Prolonged ICS 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)

Odds Ratio of Cataract Extraction According to Cumulative Treatment Duration with ICS (excluding patients with oral steroid use)

Page 16: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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 YearLow 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 YearsLow to medium dose 0.79 (0.41-1.52)High dose 0.85 (0.35-2.08)

Cumulative Treatment Duration with ICS for >2 YearsLow 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.

Page 17: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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)

Page 18: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Page 19: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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.

Page 20: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

Steroid Exposure Adjusted Relative Risk Estimate*

95% CI

Non-Exposed+

(Asthmatics only)1.0

ICS Use Only(Asthmatics only)

1.3 1.1-1.5

Oral Steroid Use Only (Asthmatics

only)

2.0 1.7-2.2

Risk of Cataracts with ICS vs. Systemic Steroids

* Each relative risk estimate is adjusted for age and sex.

+ Reference group.

Page 21: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

Jick et al. Epidemiology 2001;12(2):229-234.

Risk of Cataracts with Increasing ICS Use in All Age Groups

Page 22: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

2.71.0160.4

0.8-9.80.4-2.8

0.2-12.20.05-3.9

Age 40-60 1 prescription 2-9 10-19 ≥20

1.41.00.81.7

0.8-2.40.7-1.50.4-1.61.1-2.8

Age ≥70 1 prescription 2-9 10-19 ≥20

0.91.31.51.8

0.6-1.31.0-1.61.1-2.21.4-2.3

Page 23: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Page 24: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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.

Page 25: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

NeverEverCurrent Past Only

Baseline1.10 (1.00-1.20)1.15 (1.03-1.27)0.98 (0.84-1.14)

0.0490.010.8

Systemic Steroid Use and Consultation Rate as Confounders

Page 26: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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)

Baseline0.99 (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 None 1-9 10-19 20-29 30-39 ≥ 40

Baseline1.03 (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)

Page 27: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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.

Page 28: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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.

Page 29: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

Uboweja et al. Fund & Clin Pharm 2006;20:305-309.

Pooled OR 1.48 (95% CI 1.30-1.68)

Results of Meta-Analysis

Funnel Plot

Page 30: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Key Conclusions from Meta-Analysis

Page 31: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Further Considerations

Page 32: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Page 33: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

Ciclesonide: A Non-Halogenated ICS

Rossi et al. Pulm Pharm & Therap 2007;20:23-35.

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

Page 34: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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)

Favorable Physiochemical Properties of Ciclesonide

Page 35: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Clinical Trials To-Date Support Efficacy and Safety of Ciclesonide

Page 36: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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

Page 37: Cataracts: Unforeseen Complication of Inhaled Corticosteroids

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.