Ji Kim PS3May 7, 2010

ObjectiveDescribe the association between corticosterids/

immunosuppressions and PTDM

Explain the treatments of PTDMOral agents: biguanides, sulfonylureas,

meglitinides, thiazolidinedionesInsulin

Introduction to Diabetes MellitusDiabetes mellitus (DM)- a syndrome that is caused by a

relative or absolute lack of insulin.

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%

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/dlSymptoms of DM and randomplasma glucose ≥ 200 mg/dl

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 Transplant Associated

NonmodifiableAgeGenderRace/ethnicityFamily history

Potentially modifiableObesityPhysical inactivityHepatitis C

NonmodifiableInherited and acquired defects in insulin sensitivity

Potentially modifiableWeight gainGlucocorticoidsCalcineurin inhibitorsSirolimus

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: JR34 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 skinCellulitis of the footStatus post spelenectomy HTN HyperlipidemiaNo 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 (trade)

Total dose (mg/interval)

MOA Comments

Metformin (Glucophage)

500-850mg BID/TID

•↓ hepatic glucose output (Primary)

•↓ insulin resistance in periphery (secondary)

•↓ or delayed absorption of carbohydrates

•First line treatment in Type 2 patients

•Lactic acidosis (rare)

•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)

Glyburide (Micronase/Diabeta)

Glimepiride (Amaryl)

2.5-20mg QD/BID

2.5-10mg QD/BID

1-8mg QD

•↑ Insulin secretion from the Beta cells of pancreas

•↓ insulin resistance

•↓ hepatic glucose output

•Hypoglycemia particularly with renal dysfunction

•Use cautiously in elderly and those with ↓ renal function

•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

60-120mg TID

↑ Insulin secretion from Beta cells of pancreas

•Hypoglycemia particularly with renal dysfunction

•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.

ThiazolidinedionesGeneric name (trade)

Total dose (mg/interval)

MOA Comments

Rosiglitazone (Avandia)

Pioglitazone (Actos)

4-8mg QD/BID

15-45mg QD

•↑ insulin sensitivity at the muscle by acting as an agonist on the peroxisome proliferator activated receptor gamma which results in increased glucose uptake (Primary)

•↓ Hepatic glucose production (Secondary)

•Indications for use include monotherapy, combined with metformin, sulfonuylureas, and insulin

•↓ insulin requirements and improve control

•Can be used in renal failure

•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 settingInsulin treatment is generally preferred

Superior predictability and rapid titratability Control hepatic glucose production Basal insulin preparation (intermediate/long-

acting) between mealsBolus insulin (rapid/short-acting) to control

postprandial elevations of blood glucoseUse 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 contrastSulfonylureas are most often used.

Effective, low cost, average ↓blood glucose by 20%, ↓A1c 1.1-1.9%

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, JRDate Glucose

Level(mg/dL)

Treatments

4/16/10 266 (↑ ) • Start Glipizide XL 5mg PO daily (4/16-4/20)

• Use Accu-check QAC, QHS

4/17/10 218-426 (↑ ↑)

Start Insulin Sliding scale

4/20 /10

172 (↑ ) •Blood sugar elevated while patient is on prednisone

•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. GlyburideBoth 2nd generation sulfonyureasGlipizide XL

Initial dose 5mg daily; increase by 5mg q 1-2 weeksDuration: 24 hours Absorption: Rapid and complete

GlyburideDose: 1.25-20mg/d QD or BIDOnset 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 dailyHold insulin sliding scale

4/27/10 60 (↓) Felt sweaty and shaky-> orange juiceHold glyburide Continue Humalog sliding scale (4/27- present)

5/1/10 312 (↑ ) Switch to glimepiride 1mg PO every other day (5/1-5/2)

5/2/10 164 (↑ ) 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. GlimepirideGlyburide

2nd generation of sulfonyureas

Glimepiride3rd generation of sulfonyureasMild reduction in insulin resistanceLess hypoglycemic effectsSafe in patients with advanced kidney diseaseDose: 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

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15 ThuApr 2010

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Glucose, POC (Whole Blood)mG

/dL

ROMERO, JOSE

Glucose, POC (Whole Blood) (mG/dL)4/17 Initiate insulin

4/27 Hypoglycemia

5/1 Switch to Glimepiride4/20

Switch to glyburide

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 tacrolimus1. Woodward RS, et al. (2003)

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)

2. Heisel O, et al. (2004) 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 GVHDYagasaki 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

SirolimusSirolimus is a potent immunosuppresant1.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 PTDMChronic 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 yearsIncidence of PTDM

STOP 8% and TAP 30.3% (p=0.04)

Back to the Case, JRJR is on prednisone, tacrolimus, and sirolimus

since August 2004City of Hope protocol for GVHD patientsSo many options: making the right choice for JR?

May 5, 2010Glu= 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 recommendationIf inadequate response to maximal dose (8mg), then

combination therapy with TZDs may be considered.

Insulin therapyTraditional basal-bolus insulin regimens, such as

glargine/detemir insulin combined with rapid-acting, may be considered.

Tailoring immunossupressionConversion to cyclosporine may be considered.

Therapeutic lifestyle modificationsDiet-limited intake of calories, carbohydrates, and

saturated fatsExercise-aerobic activity, resistance training

ConclusionPTDM 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???