Ji Kim PS3
May 7, 2010
Objective
 Describe the association between corticosterids/
immunosuppressions and PTDM
 Explain the treatments of PTDM
 Oral agents: biguanides, sulfonylureas, meglitinides,
thiazolidinediones
 Insulin
Introduction to Diabetes Mellitus
 Diabetes mellitus (DM)- a syndrome that is caused by a relative or
absolute lack of insulin.
Normoglycemia
IFG or IGT (Pre-diabetes)
DM
FPG < 100 mg/dl
FPG 100 – 125 mg/dl (IFG)
FPG ≥ 126 mg/dl
2-h PG < 140 mg/dl
2-h PG 140 – 199 mg/dl (IGT)
2-h PG ≥ 200 mg/dl
Symptoms of DM and random
plasma glucose ≥ 200 mg/dl
 Glycated hemoglobin (A1C) is a form of hemoglobin used primarily to
identify the average plasma glucose concentration over prolonged periods
of time.
 A1C goal <7%
ADA guideline
 Insulin- made from beta cells of pancreatic islets of Langerhans
PTDM incidence and risk factors
 In the 12 studies of kidney transplantation, incidence of PTDM
estimates ranged from to 2 to 50%.
 Immunosuppression regimen explained 74% of the variability in the 12
months cumulative incidence (P =0.0004). (Victor M. Montori et al 2002)
 Risk factors
Preexisting
Nonmodifiable
Age
Gender
Race/ethnicity
Family history
Potentially modifiable
Obesity
Physical inactivity
Hepatitis C
Transplant Associated
Nonmodifiable
Inherited and acquired defects
in insulin sensitivity
Potentially modifiable
Weight gain
Glucocorticoids
Calcineurin inhibitors
Sirolimus
Kasiske BL et al. 2001
What is PTDM?
 PTDM has emerged as a major adverse effect of
immunosuppressive drugs.
 Corticosteroids
 Affects glucose metabolism by increasing hepatic glucose production and
by reducing peripheral tissue insulin sensitivity
 Related to the dose and the duration of therapy
 Calcineurin inhibitor (cyclosporine, tacrolimus )
 Predominantly by impairimng beta cell insulin

Tacrolimus is concentrated in the pancreas and it may inhibit
pancreatic insulin secretion.
 mTOR inhibitor (sirolimus)

Long-term mTOR inhibition impairs activation of IRS-1 and AKT and
augments insulin resistance and β cell dysfunction
Goldberg et al. 2007 &
Pavlakis et al. 2008
PATIENT: JR
 34 yo male with a PMH of severe aplastic anemia, status
post unrelated donor stem cell transplant on July 2004
 PMH:
 Chronic GVHD involving the mouth, eyes, liver, and skin
 Cellulitis of the foot
 Status post spelenectomy
 HTN
 Hyperlipidemia
 No hx of DM
 Admitted on April 13, 2010, for the lesion in the left foot
with blisters
 Notable Medications
 Prior to admission
 Prednisone 20mg PO every other day
 Sirolimus 1mg PO every other day
Tacrolimus 1mg PO two times a day
 Admission
 Zosyn 3.375g IV Q 6 h
 Levofloxacin 750mg/150ml Bag IV QPM
 LABS
 Prior to Admission
 2/7/09 Glu level= 167 (↑ )
 2/28/10 Glu level= 191 (↑ )
 3/2/10 Glucose level= 168 (↑ )
 Admission
 4/13/10 Glucose level= 237 (↑ )
 4/14/10 Glucose level=180 (↑ )

 Ht=5’6”, Wt=50kg, Scr=1.06 (4/14)
 IBW= 63.8kg, CrCL= 69 ml/min
 PTDM has been clearly associated with an elevated
risk for serious infections, acute graft rejection,
and even death.
 As diabetes has a negative impact on patient and
graft outcome, the transplant practitioner must be
cautious in screening and managing diabetes after
transplantation.
 Let’s focus on the therapeutic management of
PTDM!!
Therapeutic management of DM
 Biguanides
Generic name Total dose
(trade)
(mg/interval)
MOA
Comments
Metformin
(Glucophage)
•↓ hepatic glucose output
(Primary)
•First line treatment in Type 2
patients
•↓ insulin resistance in
periphery (secondary)
•Lactic acidosis (rare)
500-850mg
BID/TID
•↓ or delayed absorption of
carbohydrates
•Major CI is renal (Scr>1.4
females and Scr>1.5 males)
•Iodinated IV radiocontrast
dye
 Sulfonyureas
Generic
name (trade)
Total dose
(mg/interval)
MOA
Comments
Glipizide
(Glucotrol)
2.5-20mg
QD/BID
•↑ Insulin secretion from the
Beta cells of pancreas
•Hypoglycemia particularly with
renal dysfunction
Glyburide
(Micronase/
Diabeta)
2.5-10mg QD/BID
•↓ insulin resistance
•Use cautiously in elderly and those
with ↓ renal function
1-8mg QD
•↓ hepatic glucose output
Glimepiride
(Amaryl)
•Start at the low and end of the
dosing range
•Increase the dose every one or two
weeks until maximum doses are
achieved
•DDI with Beta-blockers: ↑
hypoglycemic effect
 Meglitinides
Generic name
(trade)
Total dose
(mg/interval)
MOA
Comments
Repaglinide
(Prandin)
Natgeglinide
(Starlix)
0.5-4mg TID
↑ Insulin secretion from
Beta cells of pancreas
•Hypoglycemia particularly with renal
dysfunction
60-120mg TID
•Take only with meals. Skip dose if meal
is skipped. (Good for patients who eat
irregularly)
•Major difference vs. Sulfonylureas:
Short acting & target PPG levels
• If no response from sulfonylurea, don’t
switch to a meglitinide.
 Thiazolidinediones
Generic name
(trade)
Total dose
(mg/interval)
MOA
Comments
Rosiglitazone
(Avandia)
4-8mg QD/BID
•↑ insulin sensitivity at the
muscle by acting as an
agonist on the peroxisome
proliferator activated
receptor gamma which
results in increased glucose
uptake (Primary)
•Indications for use include
monotherapy, combined with
metformin, sulfonuylureas, and
insulin
•↓ Hepatic glucose
production (Secondary)
•Can be used in renal failure
15-45mg QD
Pioglitazone
(Actos)
•↓ insulin requirements and
improve control
•Slow onset (Onset at 3 weeks; max
4-8 wks)
•No hypoglycemia
•Weight gain
• Use cautiously in pts with edema
and heart failure
•Monitor liver function test
PTDM in Hospital setting
 Insulin treatment is generally preferred
 Superior predictability and rapid titratability
 Control hepatic glucose production
 Basal insulin preparation (intermediate/long-acting)
between meals
 Bolus insulin (rapid/short-acting) to control
postprandial elevations of blood glucose
 Use sliding scale insulin to “Start low and go slow”
 Fail PO agents -> add basal insulin -> add bolus insulin
Inzucchi SE. et al. 2006
 Oral agents can safely be used in medically stable
patients
 Metformin is best AVOIDED due to contraindications

Renal/hepatic impairement, HF, pending radiology studies
involving IV contrast
 Sulfonylureas are most often used.

Effective, low cost, average ↓blood glucose by 20%, ↓A1c 1.11.9%
 Shorter-acting meglitinides provide a reasonable
inpatient alternative
 TZDs generally safe , but delayed onset of action (days to
weeks), limiting their clinical utility
Del Prato S. et al. 2006
Thiazolidinediones (TZDs)
 PROS:
 Not metabolized by the CYP3A4 system, lowering the risk for dangerous
interactions with CNIs
 Baldwin and Duffin et al. (2004)
 ↓ A1c 8.1% to 6.7% (P=0.01) in 18 posttransplant pts with rosi and
insulin/sulfonylurea
 Voltouch et al. (2005)
 4 weeks rosiglitazone treatment (8mg/d)
 Improves insulin sensitivity
 Significant decline in fasting and 2 h plasma glucose (from 6.4 to 5.8
mmol/l, P = 0.01 and from 14.2 to 10.6 mmol/l, P = 0.03
 CONS:
 Nissen SE et al. (2007)

↑ risk of MI and borderline increase in the risk of cardiovascular death
 CONTROVERSY?
Back to the Case, JR
Date
Glucose Level
(mg/dL)
Treatments
4/16/10
266 (↑ )
•
•
4/17/10
218-426 (↑ ↑)
Start Insulin Sliding scale
4/20 /10
172 (↑ )
•Blood sugar elevated while patient is on prednisone
Start Glipizide XL 5mg PO daily (4/16-4/20)
Use Accu-check QAC, QHS
•Switch to glyburide 5mg before breakfast when he is
on prednisone 20mg (4/21-4/26)
•Only use glyburide 2.5mg daily for the days when he
is not on prednisone (4/22- 4/27)
•Humalog sliding scale using 2 units for each
increment of 50mg/dl of blood glucose greater than
150mg/dl AC and HS
Glipizide XL vs. Glyburide
 Both 2nd generation sulfonyureas
 Glipizide XL
 Initial dose 5mg daily; increase by 5mg q 1-2 weeks
 Duration: 24 hours
 Absorption: Rapid and complete
 Glyburide
 Dose: 1.25-20mg/d QD or BID
 Onset of action: Serum insulin levels begin to increase 15-60
minutes after a single dose
 Duration: ≤24 hours
 Absorption: Significant within 1 hour
Date
Glucose Level
(mg/dL)
Treatments
4/25/10
268 (↑ )
Increase to glyburide 10mg after breakfast and
5mg before dinner every other day (4/25–4/29)
Change prednisone 20mg daily
Hold insulin sliding scale
4/27/10
60 (↓)
Felt sweaty and shaky-> orange juice
Hold glyburide
Continue Humalog sliding scale (4/27- present)
5/1/10
312 (↑ )
5/2/10
164 (↑ )
Switch to glimepiride 1mg PO every other day
(5/1-5/2)
Increase to glimepiride 2mg PO every other day
(5/3 to 5/4)
5/3/10
332 (↑)
5/4/10
150 (↑)
Increase to glimepiride 4mg PO every other day
(5/4 to present)
Glyburide vs. Glimepiride
 Glyburide
 2nd generation of sulfonyureas
 Glimepiride
 3rd generation of sulfonyureas
 Mild reduction in insulin resistance
 Less hypoglycemic effects
 Safe in patients with advanced kidney disease
 Dose: 1-4mg once daily; after a dose of 2mg once daily,
increase in increments of 2mg at 1 to 2 week intervals
 Maximum dose 8mg once daily
Glucose, POC (Whole Blood)
Glucose, POC(Whole Blood) (mG/dL)
450
4/17 Initiate
insulin
400
4/20 Switch
to glyburide
350
5/1 Switch to
Glimepiride
300
mG/dL
250
200
150
H
100
L
4/27
Hypoglycemia
50
15 Thu
Apr 2010
22 Thu
1 May
ROMERO, JOSE
Alternative Immunosuppressive
treatments?
 Both calcineurin inhibitors alter insulin secretion
 Effects of tacrolimus seem to be more profound and
intense compared with the CsA-induced ones
 Tacrolimus specific binding protein, i.e. FKBP-12, is
preferentially located in beta cells, leading to a strong
concentration of the drug in these cells
 CsA specific binding site (ciclophiline) is preferentially
located in the heart, the liver and kidneys.
Higher incidence in tacrolimus
Woodward RS, et al. (2003)
1.



In the 6-month, open-label, randomized, prospective
multicenter DIRECT study
Tacrolimus and CsA were compared in 567 non-diabetic
kidney graft recipents
PTDM or new IFG occurred in 26% of CsA and 33.6% in
tacrolimus (P=0.046)
Heisel O, et al. (2004)
2.


Meta-analysis of 56 prospective and randomised clinical
trials
16.6% with tacrolimus vs. 9.8% with CsA, without any
difference according to the transplanted organ
FK/MTX vs. CsA/MTX as GVHD
 Yagasaki H. et al. 2009
 Patients with severe aplastic anemia (SAA) given unrelated
donor BMT
 47 pairs matched exactly for recipient age & conditioning
regimens
 45 patients achieved engraftment in FK & 42 patient in CsA
 Results
FK/MTX
CsA/MTX
P value
Grade II-IV
acute GVHD
28.9%
32.6%
0.558
Chronic
GVHD
13.3%
36%
0.104
5-year
survival
82.8%
49.5%
0.012
Sirolimus
 Sirolimus is a potent immunosuppresant
1. Johnson RW et al.(2001) and Kreis H et al. (2000)

NODM rates were not reduced in sirolimus treated patients
2. Romagnoli J et al. (2006)

Combination CsA and sirolimus has been associated with
more NODM than CsA alone
3. Teutonico A et al. (2005)

Decreases in insulin sensitivity, pancreatice cell function,
and overall glucose tolerance have been demostrated, either
after conversion from CsA to sirolimus or after tacrolimus
elimination from a combined tacrolimus/sirolimus regimen
Effect of corticosteroid-sparing
regimen on PTDM
 Chronic high-dose steroid therapy was a major
contributing factor to the development of PTDM.
 Boots et al. (2002)
 62 patients treated with tacrolimus were prospectively
randomized to stop Prednisone 10mg after day 7
posttransplantation (STOP) or to gradually taper
steroids in 3-6months (TAP)
 Follow up of2.7 years
 Incidence of PTDM

STOP 8% and TAP 30.3% (p=0.04)
Back to the Case, JR
 JR is on prednisone, tacrolimus, and sirolimus since
August 2004
 City of Hope protocol for GVHD patients
 So many options: making the right choice for JR?
 May 5, 2010
 Glu= 206 @13:23 (↑ )
 JR is on glimepiride 4mg PO every other day, insulin
sliding scale, prednisone, tacrolimus, sirolimus
 His blood sugar is still uncontrolled, continue
following the same regimen?
My recommendation
 If inadequate response to maximal dose (8mg), then
combination therapy with TZDs may be considered.
 Insulin therapy
 Traditional basal-bolus insulin regimens, such as glargine/detemir
insulin combined with rapid-acting, may be considered.
 Tailoring immunossupression
 Conversion to cyclosporine may be considered.
 Therapeutic lifestyle modifications
 Diet-limited intake of calories, carbohydrates, and saturated fats
 Exercise-aerobic activity, resistance training
Conclusion
 PTDM results from impaired insulin secretion and
peripheral insulin resistance, largely generated by
chronic immunosuppression.
 In trasplanted patients, hyperglycemia is associated
with an increased risk for cardiovascular disease,
serious infections, graft rejection, and even death.
 PTDM should be treated in a comprehensive and
aggressive manner.
THANK YOU!!!
Any Questions???