Management of Posttransplant Diabetes Mellitus

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Management of Posttransplant Diabetes Mellitus

• Ji Kim PS3
• May 7, 2010

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Objective

• Describe the association between corticosterids/
  immunosuppressions and PTDM
• Explain the treatments of PTDM
• Oral agents biguanides, sulfonylureas,
  meglitinides, thiazolidinediones
• Insulin

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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 lt 100 mg/dl FPG 100 125 mg/dl (IFG) FPG 126 mg/dl
2-h PG lt 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 lt7

ADA guideline
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• Insulin- made from beta cells of pancreatic
  islets of Langerhans

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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
Nonmodifiable Age Gender Race/ethnicity Family history Potentially modifiable Obesity Physical inactivity Hepatitis C Nonmodifiable Inherited and acquired defects in insulin sensitivity Potentially modifiable Weight gain Glucocorticoids Calcineurin inhibitors Sirolimus Kasiske BL et al. 2001
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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
  ß cell dysfunction

Goldberg et al. 2007 Pavlakis et al. 2008
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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

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• 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 level180 (? )
• Ht56, Wt50kg, Scr1.06 (4/14)
• IBW 63.8kg, CrCL 69 ml/min

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• 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.
• Lets focus on the therapeutic management of
  PTDM!!

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Therapeutic management of DM
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• 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 (Scrgt1.4 females and Scrgt1.5 males) Iodinated IV radiocontrast dye
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• 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
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• 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, dont switch to a meglitinide.
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• Thiazolidinediones

Generic 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
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PTDM in Hospital setting

• Insulin treatment is generally preferred
• Superior predictability and rapid titratability
• Control hepatic glucose production
• Basal insulin preparation (intermediate/long-actin
  g) 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 -gt add basal insulin -gt add bolus
  insulin

Inzucchi SE. et al. 2006
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• 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 1.1-1.9
• 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
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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 (P0.01) 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?

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Back to the Case, JR
Date 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
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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

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Date Glucose Level (mg/dL) Treatments
4/25/10 268 (? ) Increase to glyburide 10mg after breakfast and 5mg before dinner every other day (4/254/29) Change prednisone 20mg daily Hold insulin sliding scale
4/27/10 60 (?) Felt sweaty and shaky-gt orange juice Hold 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)
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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

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4/17 Initiate insulin
5/1 Switch to Glimepiride
4/20 Switch to glyburide
4/27 Hypoglycemia
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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.

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Higher incidence in tacrolimus

• 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 (P0.046)
• 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

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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
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Sirolimus

• Sirolimus is a potent immunosuppresant
• Johnson RW et al.(2001) and Kreis H et al. (2000)
  
• NODM rates were not reduced in sirolimus treated
  patients
• Romagnoli J et al. (2006)
• Combination CsA and sirolimus has been associated
  with more NODM than CsA alone
• 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

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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 (p0.04)

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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 _at_1323 (? )
• 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?

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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

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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.

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THANK YOU!!!

• Any Questions???