Should all diabetics with TB be on insulin?

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

Insulin
for Diabetics
with TB

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

Rifampicin: a potent Cyt P450 inducer
lowers the serum levels of SU and metformin

Guptan & Asha. Ind J Tub 2000

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

Case report

62/M on chlorpropamide
250 mg daily
Given Rifampin
600 mg daily
Chlorpropamide
increased to 400 mg
daily

Self & Morris. Chest 1980

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

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

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

“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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

Should all diabetics with TB be on insulin?

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Should all diabetics with TB be on insulin?