Effect of Inhaled Steroids on Glucose Regulation in Asthma Patients
Condition: Asthma
MeSH terms: Asthma
Study type: Observational

Summary: 
      Inhaled steroid has been the cornerstone in the treatment of asthma, which carries a huge
      patient population worldwide including Hong Kong. In general, the safety of long-term use of
      inhaled steroid has been well documented. Yet, long-term users of such treatment carry
      increased risk of complications like cataract. In particular, the exact association of
      inhaled steroid use and development of diabetes mellitus is not known, despite a clear causal
      relationship between oral steroid use and diabetes. Therefore this epidemiology study (based
      on questionnaire and blood tests) aims to investigate the effect of inhaled corticosteroid on
      the risk of diabetes, impaired glucose tolerance and insulin resistance in adults with
      asthma. The impact of this study is expected to affect the current practice of long-term use
      of inhaled corticosteroid especially among patients with asthma.
    

Detailed description: 
      Inhaled corticosteroids (ICS) have been shown to have many side effects that are consistent
      with systemic corticosteroids, suggesting that its systemic absorption can lead to adverse
      effects in the long term users. ICS can pose a major health impact in the community,
      especially when its use has become widely accepted as mainstay treatment for asthma and
      chronic obstructive airway diseases in recent decades.

      In 1997, inhaled corticosteroids were shown to increase the risk of nuclear cataracts by
      1.5-fold and posterior subcapsular cataracts by 1.9-fold respectively. Besides, high dose ICS
      use for more than 3 months increased risk of open angle glaucoma with OR 1.44. In 1998, a
      case control study demonstrated positive association of cataract extraction in elderly ICS
      users. ICS use of more than 3 years increased cataract by 3-fold in high dose users (> 1mg
      daily budesonide dipropionate). Whereas low dose use (<1mg daily budesonide dipropionate) for
      more than 2 years increased cataract by 1.6-fold. Subsequent studies also found increased
      risk of osteoporosis in long term ICS users.

      It has been well known that systemic corticosteroid causes diabetes by inducing insulin
      resistance. Previous study showed a 2-fold increased risk of diabetes in patients using
      systemic corticosteroids.

      Nevertheless, of the many systemic side effects that are known to inhaled corticosteroids,
      its effect on the risk of diabetes has not been established yet.

      There have also been 2 small scale studies about the effect of ICS on insulin resistance
      profile, however, the study findings were also inconclusive.

      In 1987, a study of 9 subjects, given 4 weeks of inhaled budesonide dipropionate 1mg daily,
      were shown to have increase in 2-hour peak glucose level in oral glucose tolerance test, and
      also increased fasting serum insulin concentration, suggesting that ICS use was associated
      with glucose dysregulation and increase insulin resistance. Subsequently, in 1993, another
      study of 15 subjects with unstable asthma compared to 15 normal control subjects, a reduction
      in insulin resistance in patients with uncontrolled asthma was noted upon 1 month of ICS
      treatment; while the insulin resistance profile became static at 5 and 8 months of therapy.
      This study suggests that insulin resistance profile is increased in subjects with unstable
      asthma in relation to the stress induced during exacerbation. ICS can reduce insulin
      resistance profile by stabilizing asthma control.

      In terms of researches relating ICS to diabetes, there are limited studies in the elderly. In
      1998, a study showed dose dependent worsening of diabetic control in the diabetic elderly
      using high dose ICS. However, 2 subsequent case control studies conducted in 2002 failed to
      demonstrate any association of diabetes in elderly with either current use of ICS or 3 years
      uses of ICS.

      These study results are subjected to confounding by concurrent systemic corticosteroid usage,
      lack of long term users of ICS, as well as the effect of other competing causes of diabetes
      (ie. aging and obesity) being so strong in the elderly that the impact of ICS on the risk of
      diabetes might have been masked in this particular group of patients.

      So far, data is lacking in terms of the association between inhaled corticosteroids and
      diabetes, as well as impaired glucose tolerance - the pre-diabetic condition. Moreover, the
      profile of glucose regulation and potential hyperinsulinemia in ICS users with normal glucose
      tolerance is largely unexplored.

      As Asians are at increased risk of developing NIDDM, the effect of ICS in inducing diabetes
      in the Chinese might be more prominent than that for subjects in the western countries. It is
      of more clinical significance and relevance to study this issue in a Chinese dominant
      community like Hong Kong.

      Therefore, we shall investigate the effect of ICS, trying to understand its impact on the
      whole disease spectrum of insulin resistance. We shall begin with study on the risk of
      diabetes, then move on to that of impaired glucose tolerance (IGT) and finally to explore
      potential hyperinsulinemia in subjects with normal glucose tolerance who have used ICS. We
      will also put particular emphasis on the younger Chinese population, where the impact of age
      and obesity is less marked, and therefore, the effect of ICS on the risk of DM/IGT/
      hyperinsulinemia can be better manifested and delineated.

      About 10% of our population has asthma and of these, 50% are on long term inhaled
      corticosteroids. While asthma is not known to cause diabetes and hence not a confounder for
      the association of ICS and DM, we shall therefore target at the adult Chinese asthma patients
      using ICS as our study subjects, and compare the risk of diabetes/IGT/hyperinsulinemia of
      this group of patients with that of the general population.

      Since diabetes mellitus is a major health problem that is strongly associated with multiple
      cardiovascular morbidity and mortality, and inhaled corticosteroid being the most commonly
      prescribed drug in treating chronic airway diseases, knowledge regarding the risk of DM in
      association with chronic ICS use will be of major impact on public health.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Asthma patients will be recruited from asthma clinic in Queen Mary Hospital, Queen
        Elizabeth Hospital, Kowloon Hospital, Kwong Wah Hospital and select matched controls at 1:1
        ratio from the general population database of Cardiovascular Risk Factor Prevalence Study 2
        (CRISPS2).
      
Biospecimen description: 
      Plasma, serum and DNA
    
Keywords: Asthma; Diabetes; Impaired glucose tolerance; Insulin resistance