Supplementary appendix

This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Riza AL, Pearson F, Ugarte-Gil C, et al. Clinical management of
concurrent diabetes and tuberculosis and the implications for patient services.
Lancet Diabetes Endocrinol 2014; 2: 740–53.
Appendix 1. Key bidirectional screening studies published after 2011
Setting Screening method Screening yield Further findings Ref.
Poor compliance of
Symptom screen patients
China, 259-804 TB cases
followed by referred to TB services; A1
hospital diabetes per 100,000
sputum smear or chest X-
clinics population
ray Screening feasible but
burdensome for staff.
Recording in diabetes
clinics
Symptom screen
India, 642-859 TB cases not structured.
followed by referral A2
hospital diabetes per 100,000
to TB services for f/u
clinics population TB screening uses
diagnostics
increased
resources but is feasible.
Correct interpretation
Site decision to complete
9.4% known of FBG in active TB
China, RBG,
diabetes; unclear. A3
TB hospitals followed by FBG if
3% newly diagnosed
and TB clinics RBG≥110 mg/dl
diabetes Need for follow up to see
if DM is persistent
Glucometer users need
training.
Logistics issues
RBG if no known
India, tertiary (glucometer strips).
diabetes, 8% known diabetes;
care A1
followed by FBG if RBG 5% newly diagnosed
hospitals and TB Poor feedback on
≥110 mg/dl. diabetes
clinics diabetes care
once referred diabetes
services

TB, tuberculosis
RBG, Random blood glucose
FBG, Fasting blood glucose
A1
Lin, Y. et al. (2012). Screening patients with Diabetes Mellitus for Tuberculosis in
China. Tropical Medicine & International Health 17(10): 1302-1308.
A2
India Diabetes Mellitus – Tuberculosis Study, G. (2013). "Screening of patients with diabetes
mellitus for tuberculosis in India." Tropical Medicine & International Health 18(5): 646-654.
A3
India Tuberculosis-Diabetes Study, G. (2013). "Screening of patients with tuberculosis for
diabetes mellitus in India." Tropical Medicine & International Health 18(5): 636-645.
Appendix 2. Screening tests for latent tuberculosis infection and potential issues with use amongst individuals with diabetes
Comparative SensitivityA5, A6
Issues of use in patients with
Test Mode of action direct cost,A4 Downfalls
Specificity A5, A6 diabetes
time
Induration following 77% Need training to
TST intra-dermal Low, 3 days administer. Requires a Decreased immune response
tuberculin injection 97% follow-up patient visit in diabetes may lower sensitivity;
85% sparse evidence on use in
Immune reactivity detected individuals with diabetesA7
IGRA High,1 day* Requires lab capacity
from blood sample 96%
TST, Tuberculin Skin Testing
IGRA, Interferon Gamma Release Assay
*depending on frequency of Interferon-gamma reading
A4
Deuffic-Burban, S., et al., Cost-effectiveness of QuantiFERON TB test vs. Tuberculin skin test in the diagnosis of latent tuberculosis infection.
The International Journal of Tuberculosis and Lung Disease, 2010. 14(4):471-481

Best estimates for sensitivity and specificity taken from:

A5
Trajman, A., R.E. Steffen, and D. Menzies, Interferon-Gamma Release Assays versus Tuberculin Skin Testing for the Diagnosis of Latent
Tuberculosis Infection: An Overview of the Evidence. Pulm Med, 2013.
A6
Pai, M., A. Zwerling, and D. Menzies, Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update.
Annals of Internal Medicine, 2008. 149(3): p. 177-184.
A7
Faurholt-Jepsen D, Aabye MG, Jensen AV, et al. Diabetes is associated with lower tuberculosis antigen-specific interferon gamma release in
Tanzanian tuberculosis patients and non-tuberculosis controls. Scandinavian journal of infectious diseases 2014
 Appendix 3. Effect of rifampicin on the exposure (AUC) to antidiabetic drugs
Change in Additional
Metabolic
Antidiabetic drug exposure Transporters comments or
enzymes
(AUC) citations
no effect no published
Insulin None ··
anticipated studies
strong
Tolbutamide ·· ·· *
decrease
OATP2B1, P-gp,
Glibenclamide -39% CYP2C9 *
Sulphonylureas MRP1, BCRP
Gliclazide -70% CYP2C9 ·· *
Glimepiride -34% CYP2C9 ·· *
Glipizide -22% CYP2C9 ·· *
OCT1,2,3,
possible A8
Biguanides Metformin None MATE 1-2,
interference
PMAT, P-gp
-57%, -
Repaglinide 31%, CYP3A4, OATP1B1 *
Meglitinide
-50%
analogues
CYP2C8
Nateglinide -24% ·· *
CYP2C9,
CYP3A4
Thiazolidine Rosiglitazone -54%, -65% P-gp *
CYP2C8
diones
Pioglitazone -54% CYP2C8 ·· *
GLP-1 receptor Liraglutide no effect no published
None ··
agonist Exenatide anticipated studies
-76% in
saxagliptin
A9
DPP-4 inhibitor Saxagliptin -27% total CYP3A4 P-gp
moiety
exposure
Minor
Sitagliptin no effect hOAT3,OATP4
(CYP3A4, *
anticipated C1, P-gp
CYP2C8)
No effect
Vildagliptin None P-gp *
anticipated
Minor product
Linagliptin -40% P-gp
(CYP3A4) inform
None
product
SLGP inhibitor Dapaglifozine -22% (phase II ··
inform
metabolism)
*The table is based upon previously published tables in Tornio A, Niemi M, Neuvonen P, Backman J.
Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical
implications. Trends Pharmacol Sci 2012; 33(6): 312-22 and Ruslami R, Aarnoutse RE, Alisjahbana
B, van der Ven AJ, van Crevel R. Implications of the global increase of diabetes for tuberculosis
control and patient care. Tropical Medicine & International Health 2010; 15(11): 1289-99. Where
appropriate further comments or citations are provided for supporting evidence.

··, no information was available

AUC, area under the curve
GLP-1 receptor agonist, Glucagon-like peptide-1 receptor agonist
DPP-4 inhibitor, Dipeptidyl peptidase-4 inhibitor
SLGP inhibitor, sodium-glucose cotransporter inhibitor
CYP, cytochrome P450
OCT, organic cation transporter
MATE, multidrug and toxin extrusion antiporter
PMAT, plasma membrane monoamine transporter
P-gp, P-glycoprotein
OATP, organic anion transporting polypeptide
MRP, multidrug resistance protein
BCRP, breast cancer resistance protein
OAT, organic anion transporter
A8
Cho S, Yoon J, Lee M, et al. Rifampin enhances the glucose-lowering effect of metformin and
increases OCT1 mRNA levels in healthy participants. Clinical Pharmacology & Therapeutics
2011; 89(3): 416-21.
A9
Upreti VV, Boulton DW, Li L, et al. Effect of rifampicin on the pharmacokinetics and
pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in healthy subjects. Br J Clin
Pharmacol 2011; 72(1): 92-102.