Lectured delivered at the 2010 Philippine Coalition Against Tuberculosis annual convention

1. TB and Diabetes:
Should all diabetics with
TB be on insulin?
Iris Thiele Isip Tan MD, FPCP, FPSEM
Clinical Associate Professor, UP College of Medicine
Section of Endocrinology, Diabetes & Metabolism, UP-PGH
http://www.endocrine-witch.info

2. Insulin
for Diabetics
with TB

3. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

4. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

5. Rifampicin: a potent Cyt P450 inducer
lowers the serum levels of SU and metformin
Guptan & Asha. Ind J Tub 2000

6. Placebo
Rifamipicin
Rifampicin can induce CYP2C9-mediated metabolism
Modest reduction of plasma glimepiride concentration
“probably of limited clinical significance”
Niemi et al. Br J Clin Pharmacol 2000;50:591-595

7. Case report
62/M on chlorpropamide
250 mg daily
Given Rifampin
600 mg daily
Chlorpropamide
increased to 400 mg
daily
Self & Morris. Chest 1980

8. Case report
65/M on gliclazide 80 mg daily
FPG 6.4 mmol/L
HbA1c 5.4%
Atypical mycobacteriosis
Rifampicin, INH, EMB, Clarithromycin
FPG increased to 11.3 mmol/L
Gliclazide increased up to 160 mg daily
When rifampicin discontinued, gliclazide reduced to 80 mg
daily (HbA1c 5.6%)
Sellers & Dean. Diabetes Care 2000

9. SU and
Metformin
contraindicated
in liver
disease
Drug-induced hepatitis with TB treatment
Prevalence: 9.7% (Malaysia) & 12% (HK)
Alcohol abuse and chronic hepatitis
are independent risk factors
Marzuki et al. Singapore Med J 2008;49(9):688
Yew et al. Eu Resp J 1196;(9):389-90

10. Metformin can cause anorexia and GI discomfort
1930’s case series: giving insulin for weight gain
Photo from Seattle Municipal Archives
Accessed from http://www.flickr.com

11. “The use of insulin to cause a gain in
weight in undernourished children and
in lean but otherwise healthy adults is
now a well-established procedure. It
seems reasonable therefore to try its
effects in undernourished persons
suffering from pulmonary tuberculosis.”
Heaton TG. Can Med Assoc J 1932;498-501

12. Conclusion
“Insulin has a real place in the treatment of chronic
forms of pulmonary tuberculosis, febrile or afebrile, if
the patient is undernourished. In some such cases
insulin is the best drug treatment we have.”
Heaton TG. Can Med Assoc J 1932;498-501

13. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

14. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

15. Immunologic abnormalities Pulmonary physiologic
in diabetes dysfunction
Abnormal chemotaxis, adherence,
phagocytosis and microbicidal Diminished bronchial reactivity
function of PMNs
Decreased peripheral monocytes Reduced elastic recoil and lung
with impaired phagocytosis volumes
Poor blast transformation of
Reduced diffusion capacity
lymphocytes
Occult mucus plugging of
Defective C3 opsonic function
airways
Reduced ventilatory response
to hypoxemia
Worsened by
hyperglycemia
Guptan & Shah. Ind J Tub 2000

16. TB infection produces
glucose intolerance that
improves or normalizes
with TB treatment
Not specific to TB,
also seen in pneumonia
Jawad et al. J Pakistan Med Assoc 1995;45(9):237-8

17. n=496
Mycobacterial clearance from sputum is delayed during the
first phase of treatment in patients with diabetes
Diabetes: independent risk factor for a 5-delay in
mycobacterial clearance within first 60 days
Restrepo et al. Am J Trop Med Hyg 2008;79(4):541-4

18. Diabetes increased risk of
active pulmonary TB only in
those with HbA1c >7%
Active Adj HR 3.11
[95%CI 1.63-5.92, p =0.001)
Culture confirmed Adj HR 3.08
[95%CI 1.44-6.57, p =0.004)
Pulmonary Adj HR 3.11
[95%CI 1.79-7.33, p <0.001)
Leung et al. Am J Epid 20008;167:1486-94

19. Diabetics had 6.5x
higher odds [95%CI 1.1-3.80,
p=0.039] of dying from TB
than non-diabetics
Relationship between severity
of diabetes and TB outcomes
could not be evaluated
Unclear if tight diabetes control would
have a positive impact on treatment
outcomes of those with active TB
Dooley et al. Am J Trop Med Hyg 20009;80(4):634-9

20. Qing Zhang et al. Jpn J Infect Dis 20009;62:390-391

21. Qing Zhang et al. Jpn J Infect Dis 2009;62:390-391

22. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

23. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

24. Management of Coexistent TB and DM
Patients with poor diabetic control should be
hospitalized for stabilizing their blood sugar level.
Ideally, insulin should be used to control blood sugar
levels.
Oral hypoglycemics should be used only in cases of
mild diabetes. Drug interaction with rifampicin should
be kept in mind.
Goals of therapy: FPG 120 mg/dL and HbA1c <7%
Guptan & Shah. Ind J Tub 2000

25. Indications for insulin in type 2 diabetes with TB
Chronic and severe tuberculosis infection
Loss of tissue and function of pancreas
Requirement of high calorie, high protein diet
Interactions and adverse effects of anti-TB drugs
Associated hepatic disease
Contraindications for oral antidiabetic drugs
Aging
Rao PV. Int J Diab Dev Countries 1999

26. Brazilian
Thoracic
Association
2009
TB in Diabetics
“Consider extending treatment to 9 months and replace
oral hypoglycemic agents with insulin during treatment
(keep fasting glycemia <160 mg/dL).”
BTA Committee on Tuberculosis & BTA Tuberculosis Working Group
J Bras Pneumol 2009;35(10):1018-1048

27. Who should be started on insulin?
On Metformin with A1c >8.5%
Not reaching A1c target of OHA combination therapy
Kidney/liver dysfunction where OHA is contraindicated
Severe uncontrolled diabetes with catabolism
ADA-EASD 2008 Algorithm. Diabetes Care 31:1-11, 2008

28. Who should be immediately started on insulin?
Severely uncontrolled diabetes with catabolism
Fasting BG >13.9 mmol/L (250 mg/dL)
Random BG consistently > 16.7 mmol/L (300 mg/dL)
A1c > 10%
Presence of ketonuria
Symptomatic diabetes: polyuria, polydipsia, weight loss
ADA-EASD 2008 Algorithm. Diabetes Care 31:1-11, 2008

29. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

30. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

31. Glycemic Targets for Type 2 Diabetes
ADA-
Healthy ADA 1 AACE 3 IDF 4
EASD 5
Hba1c (%)* <6.0 1 <7.0 + <6.5 <6.5 <7.0 +
FBG, mmol/L <5.6 2 5.0-7.2 <6.0 <6.0 3.9-7.2
(mg/dL) (<100) (90-130) (<110) (<110) (70-130)
PPBG, mmol/L <7.8**2 <7.8 <8.0** <10
<10.0**
(mg/dL) (<140) (<140) (<145) (<180)
*DCCT-referenced assays: normal range 4–6%; **1–2 hours postprandial. †ADA and ADA/EASD guidelines
recommend HbA1C levels ‘as close to normal (<6%) as possible without significant hypoglycemia’1,5
ADA=American Diabetes Association; AACE=American Association of Clinical
Endocrinologists;IDF=International Diabetes Federation; EASD=European Association for the Study of
Diabetes.
1. 1 American Diabetes Association. Diabetes Care 2006;29(suppl 1):S4–S42.
2. 2 American Diabetes Association. Diabetes Care 2006;29(suppl 1):S43–8.
3. 3 American Association of Clinical Endocrinologists. Endocr Pract 2002;8(suppl 1):40–82.
4. 4 International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International
Diabetes Federation, 2005. http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf.
5. 5 Nathan D. et al. Diabetologia 2006;49:1711–21.

32. Expected Decrease in A1c
Step 1: initial 9.0
Basal insulin
•Lifestyle change: 1-2% 8.5
SU TZD
•Metformin: 1.5% 8.0
Step 2: additional therapy 7.5
•Basal insulin: 1.5-2.5% (at least) 7.0
•Sulfonylureas: 1.5% 6.5
•TZDs: 0.5-1.4% 6.0
•GLP-1 agonist: 0.5-1.0% HbA1c
ADA-EASD Consensus. Nathan et al Diabetes Care 2006

33. 1 3
Drug
effects/ Indications
interactions for insulin
Insulin
2 for Diabetics 4
with TB
Immune Treatment
dysfunction goals

34. Thank You!
http://www.endocrine-witch.info