POST-TRANSPLANT DIABETES MELLITUS

Elias S. Siraj, M.D., FACP, FACEAssociate Professor of MedicineDirector, Clinical Endocrinology

Program Director, Endocrinology Fellowship Temple University School of Medicine & Hospital

Philadelphia, PA

Post-Transplant Diabetes Mellitus (PTDM)

• Other names– Transplant Induced Diabetes

– New-onset Diabetes after Transplant

• Definition– Diabetes diagnosed / developed

after organ transplant

– No pre-existing diabetes

Definition and Incidence of PTDM : Previous Studies

• Older studies lack uniform diagnostic criteria

• Newer studies: use ADA criteria for diagnosisReferences Definition of PTDM Pred/ AZA

%Pred/ CSA%

Pred/AZA/CSA%

Bourdreaux et al 2 FBG > 140 + abnormalOGTT

6.4 6.9 19.1

Meija et al 2 RBG > 200 3.3 11.2 -

Roth et al 3 FBG > 140 9.1 18.6 -

Yoshimura et al Requirement of insulin 12.8 17.1 -

Sumrani et al 3 FBG > 150 11.6 - -

Hrick et al Requirement of insulin 9.6 - 12.9

Incidence/ Prevalence of PTDM

• Exact incidence & prevalence unknown because of differences in definition

– Ranging between 4-46%

• Usually develops with in one year of Tx• Sumrani et. Al., Transplantation 1991; 51: 343

• Prevalence gradually increases over the years

• Cosio et.Al. Kidney international 2001; 59:732

0 3 6 9 12 15 18 21 24 27 30 33 36

100%

95%

90%

85%

80%

75%

70%

65%

60%

Months post-transplant

Surv

ival

free

of d

iabe

tes

N=8854 7494 6308 5240 4258

Survival Free of Post-Transplant Diabetes with 95% Confidence Intervals

(United Renal Data System)

Kasiske B, et al Am J Transplantation 2003; 3:178-85

Cost of PTDM

• Additional cost of developing PTDM after kidney transplant

– 1 year after tx: $12,000 – 13,000

– 2 years after tx: $ 19,000 – 22,000

• Woodward RS et.al. Am J Transplant 3: 590-598

PTDM: Risk Factors• General risk factors

– Increasing age

– Family hx of DM

– Obesity

– Abnormal glucose tolerance pre-Tx

– Black & Hispanic ethnic groups

• PTDM specific risk factors– Cadaveric Tx

– Certain HLA types

– Hepatitis C Virus infection

– CMV infection

– Immunosuppressive agents- Weir MR et al. Am J Kidney Dis. 1999;34:1-13- Hjelmesaeth J et.al. Diabetologia. 2004; 47:

1550-6

Ethnicity and Risk for PTDM

05

10152025

Caucasian African American HispanicInci

denc

e of

PTD

M (%

)

Ethnicity

3.6%

19.8%* 21.3%*

*P<0.01 vs Caucasian.Sumrani et al. Transplantation. 1991;51:343-347.

Age and Risk for PTDM

05

10152025303540

Age <45 Age >45

Inci

denc

e of

PTD

M (%

)

5.2%

34%

P<0.05Boudreaux JP et al. Transplantation. 1987;44:376-381.

0

10

20

30

40

50

60

70

Pre-transplant DiabetesMellitus

New-onset Diabetes afterTransplantation

Prev

alen

ce o

f Dia

bete

s (%

)

HCV +veHCV -ve

17%13%

64%

28%

p = 0.0001

Hepatitis C and Risk for PTDM

Kasiske B, et al. Am J Transplantation 2003; 3:178-85 Bloom J Am Soc of Neph 2002 13:1374-80;

Cleveland Clinic Data• Retrospective analysis

• Kidney Tx 1996-98• 209 patients who received single organ

kidney Tx (no prior hx of DM)

• Diagnosis of DM according to ADA (FBG ≥ 126, RBG ≥ 200)

• 49 patients developed PTDM (23%)

• 42 patients and 42 matched controls analyzed (matched for time of transplant)

Abacan, Chinnappa, Wojtowicz, Braun, Siraj. 65th Scientific Sessions, ADA. June 2004, Orlando, Florida

Prevalence of Risk Factors for PTDM among Cases & Controls

Abacan, Chinnappa, Wojtowicz, Braun, Siraj. 65th Scientific Sessions, ADA. June 2004, Orlando, Florida

0%

10%

20%

30%

40%

50%

60%

70%

80%

Age>/40 BMI>/30 Minority HCV Ab +

CASECONTROL

P=0.008

P=0.04 P=0.18

P=0.16

PTDM and the Immunosuppressive Regimen

• Corticosteroids

• Calcineurin inhibitors

– Cyclosporine (CsA)

– Tacrolimus

• Other

– Azathioprine (AZA)

– Mycophenolate mofetil (MMF)

– Sirolimus

PTDM and Corticosteroids• Observed in as many as 46% of renal transplant

recipients receiving higher maintenance doses1

• Lower rates reported with relatively low steroid maintenance doses2

• Risk related to dose3

• Mechanism :

– Increased insulin resistance followed by relative insufficiency of insulin production2

1Gunnarsson R et al. Transplant Proc. 1979;XI:1280-1281.2Weir MR et al. Am J Kidney Dis. 1999;34:1-13.3Hjelmesæth J et al. Transplantation. 1997;64:979-983.

PTDM and Cyclosporine• Steroid-sparing effect resulted in lower reported

incidence of PTDM after introduction of cyclosporine1

• PTDM incidence of 3% to 14% with lower doses of cyclosporine and corticosteroids1

• Mechanism:

– Primary: diminished pancreatic secretory capacity2

– Secondary: insulin resistance1Weir MR et al. Am J Kidney Dis. 1999;34:1-13.2van Duijnhoven EM et al. J Am Soc Nephrol. 2002;13:213-220.

Cyclosporine and Insulin Secretion

• Evidence in animal and human studies

– very high concentration of CSA in pancreatic cells at autopsy

– decreased production of insulin

– decreased release of insulin

– decreased beta cell volume

PTDM and Tacrolimus• Was expected to reduce incidence of

PTDM secondary to reduction in dose of steroids

• Incidence of 10-40 % reported in different studies

• Tends to be more reversible than CsA• Mechanism:

– Primary: diminished pancreatic secretory capacity (> CsA)

– Secondary: insulin resistance

Woodward et al, AJT. 2003:3 1-9.

Tacrolimus and PTDM• Hirano et. al 1992 (Japan)

– Rats: FK 506 1, 5, 10 mg/kg/d for 14 days• hyperglycemia

• reduced insulin secretion

• vacuolization and degranulation of islet cells

• effects were dose dependent

• effects reversed after discontinuation of FK• Hirano et.al. Transplantation 1992; 53: 889

• Effect may be irreversible if prolonged rx (dogs)• Strasser et. Al. Metabolism 1992; 41:64

• Insulin mRNA transcription defect: dose and duration dependent

• Tamura et.al Transplantation 1995; 59: 1606

Effects of Calcineurin Inhibitors on Pancreatic Islet β Cells

Control Cyclosporine Tacrolimus

Uniform intense staining for insulin

Mild vacuolization and weaker distribution of staining in β cells

Marked swelling and vacuolization with very weak staining in β cells

Drachenberg CB et al. Transplantation 1999; 68: 396–402

Sirolimus (Rapamycine) and PTDM

– A macrolide abx : works by a different mechanism than calcineurin inhibitors

• Animals: impaired insulin secretion• Humans: possibly diabetogenic

– Recent randomized long term trial (1 year f/u)• PTDM incidence

– 7/41 on Tacro and Siro (17%)– 5/37 on Tacro and MMF (14%)– 15/45 on CSA and Siro (33%)

• Gaetano C et.al. Transplantation. 77: 252-258

Sirolimus (Rapamycine) and PTDM• Study on insulin resistance and insulin secretion

– 41 patients converted from CsA or tacrolimus to sirolimus

• Insulin sensitivity dropped (P=0.01)

• Insulin secretory response dropped (P=0.02)

• 30% increase in incidence of IGT

• 4 new patients developed DM• Tetonico A, et.al. J Am Soc Nephrol 2005; 16: 3128

• Another study– Adding sirolimus to tacrolimus increased risk of DM

– On multivariate regression analysis• Sirolimus was not an independent risk factor (P=0.09)

• Sulanc E, et.al. Transplantation 2005; 80: 945

Other Immunosuppressants and PTDM

– Azathioprine• ?no effect on glycemic control

– Mycophenolate mofetil• no effect on glycemic control

– Biological Agents: no effect on blood glucose

• Anti-thymocyte globulin (ATG)

• OKT3 (monoclonal antibodies)

Questions Regarding PTDM

• Do patients develop the same microvascular complications as in type 1 and 2 DM?

• Does it increase the risk of developing cardiovascular disease and death?

• Does it increase the risk of getting an infection and its severity?

• Does it increase the risk of graft failure?

• Does it increase risk of death?

PTDM May Be a Predictor of Increased Risk for Graft Loss

020406080

100

PTDM No PTDM

54%82%

4 ye

ars

Gra

ft Su

rviv

al (%

)

P<0.05Roth D et al. Transplantation. 1989;47:278-281.

0

20

40

60

80

100

PTDM No PTDM

PTDM Is Associated With an Increased Risk of Infection

Patie

nts

(%)

17%

54%

P<0.05Sumrani NB et al. Transplantation. 1991;51:343-347.

Patie

nt C

umul

ativ

e Su

rviv

al

Years

No diabetes after transplantation (f/u 11.0 years)

New-onset diabetes after transplantation (f/u 8.1 years)

0

0.2

0.4

0.6

1.0

0 5 10 15 20

0.8

n = 978

Patient Survival With and Without PTDM

Jindal & Hjelmesaeth, Transplantation; 2000; 70: SS58-63.Other studies: Increased RR of

death from CV ds 1.5-3

Occurrence of Complications Among Cases & Controls

Abacan, Chinnappa, Wojtowicz, Braun, Siraj. 65th Scientific Sessions, ADA. June 2004, Orlando, Florida

0%

10%

20%

30%

40%

50%

60%

70%

80%

Rejections Infections

CASES WITH PTDMCONTROL

P=0.017

P=0.033

P< 0.001

P=0.08

Diabetic Nephropathy in PTDM Patients after Kidney Tx

• 10 patients with PTDM following Kidney tx had graft biopsy– Mean of 4.5 years after Tx– Mean of 4 years after PTDM

• 5/10 (50%) had diabetic nephropathy– 4 had diffuse glomerulosclerosis– 1 had nodular glomerulosclerosis

• Koselji M et.al. Transplantation Proceedings. 35: 2919-21

Impact of Diabetes After Transplantation

Diabetes after transplantation

Graft function

and survival

Proposed mechanisms• Diabetic nephropathy• Hypertension• Low immunosuppressant doses

Patientsurvival

Risk of CVD

Proposed mechanisms• Increased infections• Increased risk of CVD

Proposed mechanisms•Glucose intolerance• Insulin resistance• Dyslipidemia• Hypertension

Davidson, Wilkinson et al. New-Onset Diabetes after Transplantation: 2003 International Consensus Guidelines. Transplantation 2003 75:SS1-SS24.

Management Challenges

• Limited objective data regarding:

– when to start treatment

– which agents to use

– how long to treat

– what blood glucose targets to aim for

– how to adjust treatment during tapering of steroids

Non-pharmacologic Measures

• Use the minimum dose of steroid/ immunosuppressive agents possible

– equivalent doses of most steroids have similar effect on glycemic control

• Diet : CHO may have to be reduced to <50%

• Exercise

Oral Agents and Incretins

• Inadequate data regarding the relative efficacy of the different oral agents

• All the following groups may be used in different circumstances– Secretagogues : sulfonylureas, repaglinide,

nateglinide– Metformin– TZDs (rosiglitazone and pioglitazone)– alpha-glucosidase inhibitors: acarbose, miglitol– DPP-4 inhibitors– Incretin mimetics

Glucose Glucose absorptionabsorption

Hepatic glucoseHepatic glucoseoverproductionoverproduction

Beta-cellBeta-celldysfunctiondysfunction

InsulinInsulinresistanceresistance

Major Targeted Sites of Oral Drug Classes

DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.DeFronzo RA. Ann Intern Med. 1999;131:281–303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.

Pancreas

↓Glucose level

Muscle and fatLiver

Biguanides

TZDs Biguanides

Sulfonylureas

Meglitinides

TZDs

Alpha-glucosidase inhibitors

Gut

The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production.

DPP-4 inhibitors

DPP-4 inhibitors

Biguanides

Metformin and TZDs

• Target insulin resistance

• Onset of action is late for TZDs making them less useful for short/intermediate term

• May be used in long term

• Frequent contraindications• Metformin:Creatinine >1.4-1.5, CHF,Liver ds

• TZDs: CHF, edema states, liver ds

Secretagogues and α-glucosidase inhibitors

• Have relatively rapid onset of action

• May be used for mild-moderate hyperglycemia

– AM sulfonylurea

– Repaglinide/Nateglinide with meals• safer in mild renal impairment

– Acarbose/Miglitol with meals

• Combination of various oral agents may be used in moderate hyperglycemia

Insulin

• In patients with moderate to severe hyperglycemia or if contraindications for oral agents

• Usually rapid acting insulins with meals• 70/30 or 75/25 insulin in AM or BID

• NPH in AM and R/H at dinner

• NPH in AM (or BID) and R/H 2-3x with meals

• Lantus in AM with R/H 2-3x with meals

• Avoid large doses in late evening

Modification of Immunosuppressive Regimen

• Reduce the dose of steroids as soon as possible

• Consideration of the risk of developing new onset diabetes mellitus after transplantation should be weighed against the risk of acute rejection when choosing an immunosuppressive regimen

• Switching from tacrolimus to cyclosporine may be beneficial if diabetes develops and is difficult to control.

Davidson, Wilkinson et al. New-Onset Diabetes after Transplantation: 2003 International Consensus Guidelines. Transplantation 2003 75:SS1-SS24.

Goal of Therapy

• In short term (hospital)

– keep BG to < 110- 140 (max 180)

• In long term

– same as DM in general • preprandial BG 80-120 (< 110)

• bed time BG 100-140

• postprandial BG < 180 (< 140)

• HbA1c < 7% (< 6.5%)

Conclusions• PTDM is associated with significant morbidity

and mortality.

• Given the availability of simple diagnostic methods and the benefits of strict glycemic control, patients should be screened frequently.

• Management is multifaceted and aimed at both treatment and prevention of complications.

• Evaluation of patient at risk for PTDM and its complications is an important consideration in initial selection and subsequent modification of the immunosuppressive regimen.