TB and Diabetes:

Should all diabetics with TB be on insulin?Iris Thiele Isip Tan MD, FPCP, FPSEM

Clinical Associate Professor, UP College of MedicineSection of Endocrinology, Diabetes & Metabolism, UP-PGH

http://www.endocrine-witch.info

Insulin

for Diabetics with TB

Drug effects/

interactions

1

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

Drug effects/

interactions

1

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

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

Guptan & Asha. Ind J Tub 2000

Rifampicin can induce CYP2C9-mediated metabolismModest reduction of plasma glimepiride concentration

“probably of limited clinical significance”

PlaceboRifamipicin

Niemi et al. Br J Clin Pharmacol 2000;50:591-595

Self & Morris. Chest 1980

Case report

62/M on chlorpropamide 250 mg daily

Given Rifampin 600 mg daily

Chlorpropamide increased to 400 mg daily

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

Drug-induced hepatitis with TB treatmentPrevalence: 9.7% (Malaysia) & 12% (HK)

Alcohol abuse and chronic hepatitis are independent risk factors

SU and Metformin

contraindicated in liver disease

Marzuki et al. Singapore Med J 2008;49(9):688Yew et al. Eu Resp J 1196;(9):389-90

Photo from Seattle Municipal ArchivesAccessed from http://www.flickr.com

Metformin can cause anorexia and GI discomfort1930’s case series: giving insulin for weight gain

“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

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

Drug effects/

interactions

1

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

Drug effects/

interactions

1

Immunologic abnormalities in diabetes

Pulmonary physiologic dysfunction

Abnormal chemotaxis, adherence, phagocytosis and microbicidal function of PMNs

Diminished bronchial reactivity

Decreased peripheral monocytes with impaired phagocytosis

Reduced elastic recoil and lung volumes

Poor blast transformation of lymphocytes

Reduced diffusion capacity

Defective C3 opsonic functionOccult mucus plugging of 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

Mycobacterial clearance from sputum is delayed during the first phase of treatment in patients with diabetesDiabetes: 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

n=496

Diabetes increased risk of active pulmonary TB only in

those with HbA1c >7%

Leung et al. Am J Epid 20008;167:1486-94

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)

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

Dooley et al. Am J Trop Med Hyg 20009;80(4):634-9

Unclear if tight diabetes control would have a positive impact on treatment

outcomes of those with active TB

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

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

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

Drug effects/

interactions

1

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

Drug effects/

interactions

1

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

Association2009

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

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

Drug effects/

interactions

1

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

Drug effects/

interactions

1

Glycemic Targets for Type 2 Diabetes

Healthy ADA 1 AACE 3 IDF 4ADA-

EASD 5

Hba1c (%)* <6.0 1 <7.0 + <6.5 <6.5 <7.0 +

FBG, mmol/L (mg/dL)

<5.6 2

(<100)5.0-7.2 (90-130)

<6.0 (<110)

<6.0 (<110)

3.9-7.2 (70-130)

PPBG, mmol/L (mg/dL)

<7.8**2

(<140)<10.0**

<7.8 (<140)

<8.0**(<145)

<10(<180)

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.

*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.

Expected Decrease in A1c

Step 1: initial

•Lifestyle change: 1-2%

•Metformin: 1.5%

Step 2: additional therapy

•Basal insulin: 1.5-2.5% (at least)

•Sulfonylureas: 1.5%

•TZDs: 0.5-1.4%

•GLP-1 agonist: 0.5-1.0%

Basal insulin

6.0

6.5

7.0

7.5

8.0

8.5

9.0

SU TZD

HbA1c

ADA-EASD Consensus. Nathan et al Diabetes Care 2006

Indications for insulin

3

Immune dysfunction

2

Treatment goals

4Insulin

for Diabetics with TB

Drug effects/

interactions

1

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