The Impact of Diabetes Mellitus and Its Control on Developing Tuberculosis: A

Nationwide Longitudinal Study in Taiwan

加護病房查房日誌

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Outlines

• Background• Material and methods• Results• Discussion• Conclusions• Future works

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Background

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Global Burden of Tuberculosis

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2 billion people are estimated to be infected with Mycobacterium tuberculosis (TB).

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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.

Tuberculosis in Taiwan

5Reference: 台灣結核病防治年報 2013

率 : 每十萬人口

率 : 每十萬人口

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

Epidemiology of Diabetes Mellitus (DM)

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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

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)

DM control vs. TB-2No evidence for any association between TB and dysglycemiaIn the low TB-burden country of Denmark

Reference: A Leegaard et al, Diabetes Care 34:2530–2535, 2011

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?

10Ref: Journal of Food and Drug Analysis, Vol 15, No. 2, 2007, Pages 99-108

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

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

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Materials and Methods

Approved by the Research Ethics Committee (REC) of National Taiwan

University Hospital(NTUH REC: 201112111RIC)

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Data Source

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the Longitudinal Health Insurance Database (LHID) 2005From 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 DMA 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

Exclusion Criteria

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Index date: the date of first DM diagnosis

1 Jan 1997

Excluded: Pts with DM and index date prior 1 Jan 1997To ensure an observation period of 1 yr

Excluded: < 6 months of follow up after index dateTo ensure a sufficient observation period

Pts with TB prior to the index date were also excludedHigher risk for getting another episode of TB

Definition of DM or TB

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ICD9: 250A code: A181Exclude gestational diabetes

ICD9: 010-018A code: A020,A021

Anti-TB medications:Isoniazid, ethambutol, rifampicin, pyrazinamide…etc.

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

17Ref: PLoS One 2012; 7: e37978.

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

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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

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Factors During Time Segment

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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

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

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Results

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Selected Sample Size

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Part 1

DM vs. non DM

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Characteristics of Patients with DM and the Control Subjects

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Age 61.9±14.2 yrsMore DM patientsdeveloped TB

Curves of time to active TB among DM patients and control

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Factors associated with TB in DM patients

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Sensitivity Analysis

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Part 2

Among DM patients

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DM cases with or without TB

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Age 63.6±13.2 yrsMale dominance

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

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Time-dependent Cox proportional hazards analysis

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Sensitivity analysis

•Sensitivity analyses revealed the same results1. developing TB more than 1 year after the diagnosis of DM2. the 270-day time segment to from 450 days to 180 days prior to each outcome

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

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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

34Ref: 1. Lancet Infect Dis 2009; 9: 737–746. 2. Clin Infect Dis 2012; 54: 818–825. 3. Clin Infect Dis 2008; 47: 634–641

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

35Ref: Am Rev Tuberc 1952; 65: 1–50.. Trop Doct 1990; 20: 147–150.

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.

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

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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

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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 %

39Ref: 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.

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

40Ref: 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.

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

41Ref: PLoS One 2012; 7: e37978.

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.

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Another Study

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

Thank you for your listening

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