分享研究成果

1. The Impact of Diabetes Mellitus and Its
Control on Developing Tuberculosis: A
Nationwide Longitudinal Study in Taiwan
加護病房 房日誌查
1

2. Outlines
• Background
• Material and methods
• Results
• Discussion
• Conclusions
• Future works
2

3. Background
3

4. Global Burden of Tuberculosis
4
2 billion people are estimated to be infected
with Mycobacterium tuberculosis (TB).
1/3
In 2014, estimated 9.6 million new cases of TB,
1.5 million people died from TB.
Reference: World Health Organization: Global Tuberculosis Report.
In Book Global Tuberculosis Report City: World Health Organization; 2015.

5. Tuberculosis in Taiwan
5
Reference: 台灣結核病防治年報 2013
率 : 每十萬人口
率 : 每十萬人口

6. Risk Factors of TB
• Age
• Male gender
• Low socioeconomic
status
• Malnutrition
• Substance abuse
• Silicosis
• Human
immunodeficiency virus
infection (HIV infection)
• Malignancy
• Diabetes
• Relative risk or hazard
ratio: 1.6 to 6.8
• Renal disease
• Celiac disease
• Gastrectomy
• Transplant
• Corticosteroids
• Tumor necrosis factor
inhibitors
6Reference: C Robert Horsburgh Jr. MD, MUS. Epidemiology of turberculosis. In: UpToDate, Elinor, LB MD (Ed),
UpToDate, Waltham, MA, 2013

7. Epidemiology of Diabetes Mellitus (DM)
7
422 million adults had diabetes, Prevalence Rate: 8.5 %
8.4 % in W Pacific
8.3 % in the Americas 7.1 % in Africa 8.6% in South-East Asia
7.3 % in Europe
Reference: World Health Organization: Global Report on Diabetes; 2016.
10 % in Taiwan,
2015

8. DM control vs. TB-1
The evidence is lacking
Reference: CC Leung et al, American Journal of Epidemiology 2008, 167: 1486-1494
HbA1C >=7% vs. no DM:
Active TB: RR 1.97 (95% CI 1.51-2.57)

9. DM control vs. TB-2
No evidence for any association between TB and dysglycemia
In the low TB-burden country of Denmark
Reference: A Leegaard et al, Diabetes Care 34:2530–2535, 2011

10. Taiwan’s National Health Insurance
Research Databases
Strength
• Large sample size
– 97% of Taiwan’s population
• Relatively inexpensive
• Real-world practice
– Medical service utilization
– Prescription drug use
• Longitudinal histories
Weakness
• Over-the-counter drugs?
• A secondary database
• Lag time
• Disease severity?
• Laboratory data?
10
Ref: Journal of Food and Drug Analysis, Vol 15, No. 2, 2007, Pages 99-108

11. 11
Impact factor: 2.908, Ranking: Pharmacology & Pharmacy 81 out of 253, 32 %

12. Purpose
• To investigate the impact of DM and its
control on the risk of developing active TB
– The National Health Insurance Research
Databases(NHIRD)
– Time-dependent Cox proportional hazards models
12

13. Materials and Methods
Approved by the Research Ethics
Committee (REC) of National Taiwan
University Hospital
(NTUH REC: 201112111RIC)
13

14. Data Source
14
the Longitudinal Health Insurance Database (LHID) 2005
From 1996 to 2007
DM vs. non-DM
(case-control study,
Age, sex and time of entry,
1:1 in case number)
DM and co-morbidities
The risk factors for developing TB
Among DM
A Time-dependent approach
DM medications adherence
(weakness: no lab data (HbA1c) )
All selected cases were followed up until active TB developed,
31 Dec. 2007 or lost to follow up

15. Exclusion Criteria
15
Index date
: the date of first DM diagnosis
1 Jan 1997
Excluded:
Pts with DM and index date prior 1 Jan 1997
To ensure an observation period of 1 yr
Excluded:
< 6 months of follow up after index date
To ensure a sufficient observation period
Pts with TB prior to the index date were also excluded
Higher risk for getting another episode of TB

16. Definition of DM or TB
16
ICD9: 250
A code: A181
Exclude gestational diabetes
ICD9: 010-018
A code: A020,A021
Anti-TB medications:
Isoniazid, ethambutol, rifampicin, pyrazinamide…etc.

17. Co-morbidities
• Malignancy
• End-stage renal disease (ESRD)
• Chronic obstructive pulmonary disease
(COPD)
• Pneumoconiosis
• Liver cirrhosis
• Autoimmune diseases
• Acquired immunodeficiency disese
• The low income group
– Annual household income < 4,500 US dollars 17
Ref: PLoS One 2012; 7: e37978.

18. Statistical Analysis-1
• Part 1 (case control)
– Inter-group differences
• Numerical variables: independent samples t-test
• Categorical variables: chi-square or Fisher’s exact test
– Curves of time-to-active TB
• Kaplan-Meier method and the log-rank test
– Factors for developing TB
• Cox-regression analysis
– Sensitivity analysis
• In different sub-population with different follow-up
duration 18

19. Statistical Analysis-2
• Part 2 (Among DM patients)
– Factors for developing TB
• The time-dependent Cox proportional hazards model
– Time-dependent variables:
» Age, co-morbidities, use of systemic corticosteroids, oral
hypoglycemic agents (OHAs), and insulin,
» Adherence to anti-DM medications, DM associated
admissions
– Time-independent variables: sex
– Sensitivity analysis
• DM pts need > 90 days of DM medications
• All analyses were performed by using the SAS
19

20. Factors During Time Segment
20
TB event date-90 days-270 days
• OHAs: defined daily doses (DDDs)
• Adherence to anti-DM medication, continuous variable, 0 to 1
• The proportion of days covered by anti-DM medication prescribed at the
outpatient clinic within 270-day time segment
• The average OHA daily dose
• The number of days covered by systemic corticosteroids
• The maximum average daily dose (MADD)
• The maximum of the average doses of OHAs and insulin for every 90
consecutive days
• Insulin use
• Insulin dose during admission and the outpatient clinic (continuous variable)
• Insulin use during admission and at the outpatient clinic (categorical variable)
• The number of admissions with compatible DM diagnoses

21. Delayed Diagnosis of TB and
Reactive Hyerglycemia
• Two sensitivity analyses
– Risk factors for developing of TB > one years after
the diagnosis of DM
– The 270-day time segment
• 360 to 90 days, 450 to 180 days prior to each outcome
event
21

22. Results
22

23. Selected Sample Size
23

24. Part 1
DM vs. non DM
24

25. Characteristics of Patients with DM and
the Control Subjects
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Age 61.9±14.2 yrs
More DM patients
developed TB

26. Curves of time to active TB among DM
patients and control
26

27. Factors associated with TB in DM patients
27

28. Sensitivity Analysis
28

29. Part 2
Among DM patients
29

30. DM cases with or without TB
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Age 63.6±13.2 yrs
Male dominance

31. DM patients who developed TB received higher
doses of insulin, OHAs, systemic corticosteroids
31

32. Time-dependent Cox proportional
hazards analysis
32
Sensitivity analysis
•Sensitivity analyses revealed the same results
1. developing TB more than 1 year after the diagnosis of DM
2. the 270-day time segment to from 450 days to 180 days prior to each outcome

33. Discussion
• Three major findings
– DM is an important risk factor of TB, and its effect
persists for at least 5 yrs
– The risk of TB parallels the severity of DM
• Measured by the number of DM-related admissions,
MADD of OHA and insulin use during admission
– Some cases of TB may be prevented by promoting
adherence to anti-DM medication
33

34. Increased the Risk of TB in DM
Patients
• Risk in previous studies: 1.48 to 6.8
– Our study: 1.293 (1.154-1.449)
– Taiwan’s 2001 National Health Interview Survey:
2.09 (1.10-3.95)
• Pros: including environmental, educational and socio-
economic conditions
• Cons: no autoimmune disease, malignancy, ESRD, liver
cirrhosis
• Mechanisms
– The compromised immune response in diabetic pts
34
Ref: 1. Lancet Infect Dis 2009; 9: 737–746. 2. Clin Infect Dis 2012; 54: 818–825. 3. Clin Infect Dis 2008; 47: 634–641

35. OHA and insulin
• Previous studies:
– Insulin dependence is a marker of disease severity
and predictive of increased risk of TB
• The daily dose of OHA and insulin continued
to increase after DM was diagnosed.
• Higher daily dose of OHA
– Worse therapeutic response and longer duration
of DM
– Increase the risk of developing TB
35
Ref: Am Rev Tuberc 1952; 65: 1–50.. Trop Doct 1990; 20: 147–150.

36. DM-associated Admissions and Insulin
• Higher HbA1c: higher risk of admissions
• Insulin use during admission
– A surrogate maker of poorly controlled DM
• DM-associated admissions
– Diabetic ketoacidosis and non-ketotic hyper-
osmolar syndrome
– Poor DM control
– Increase the risk of contact with TB cases
36Ref: 1. Arch Intern Med 1999; 159: 2053–2057. 2. Arch Intern Med 1997; 157: 669–675. 3. Clin Chest Med 1989;
10: 397–405.

37. Insulin Dose during Admission or
the Outpatient Clinic
• Those are not independent risk factors
– Higher dose reflects a more aggressive use of
insulin
– A higher probability of good sugar control
37

38. Delayed TB Diagnosis
• Similar final statistical models:
– Sensitivity analysis of developing TB > one years
after diagnosis of DM
– Adjusting the 270-day time segment prior to each
outcome event
• Suggest that delayed TB diagnosis and
reactive hyperglycemia
– NOT alter the impact of DM and its control on the
risk of TB
38

39. The Protective Effect of Adherence
to Anti-DM Medications
• Even greater in DM pts frequently requiring
anti-DM medication
• Poor adherence to anti-DM treatment
– Poor diabetes control
– Increased susceptibility to infection
• Similar results in Hong Kong
– HbA1c > 7 %
39
Ref: 1. Clin Ther 2011; 33: 74–109 . 2. Diabetes Care 2008; 31: 916–921 3. QJM 2007;
100: 345–350 4. Am J Epidemiol 2008; 167: 1486–1494.

40. Other Risk Factors
• Age: lower HR than that of Baker’s study
– The prevalence of underlying co-morbidity and
the number of DM-associated admissions often
increased as age increases
• Male sex, COPD, DM, ESRD and the use of
systemic corticosteroids are also well-known
predisposing factors of TB
– Smoking (not available in NHIRD), TB and COPD
40
Ref: 1. Clin Infect Dis 2012; 54: 818–825. 2. Am J Respir Crit Care Med 2009; 180: 475–480. 3. Am J
Respir Crit Care Med 2007; 176: 532–555 4. Semin Dial 2003; 16: 38–44.

41. Limitations
• Lack of culture and laboratory data for the
diagnosis of TB
– Diagnosis of TB has been verified
– Sensitivity analysis
• Without lifestyle information
– DM patients may quit smoking and drinking after
diagnosis
– It may reduce the risk of TB
• Using adherence, not HbA1c to measure DM
control
– Prospective clinical studies 41
Ref: PLoS One 2012; 7: e37978.

42. Conclusions
• This study confirms the association of DM and
TB and complements previous reports by
showing that the risk of developing TB
parallels the severity of DM.
• Some cases of TB can be prevented by
promoting adherence to anti-DM medication.
• Healthcare providers should keep a high index
of suspicion and periodically screen for active
TB in DM patients.
42

43. Another Study
43
Ref: PLOS Medicine | DOI:10.1371/journal.pmed.1002072 August 9, 2016

44. Thank you for your listening
44