I did not NODAT… · History •First described by Starzl in 19641 –Era of Steroids (up to...

I did not NODAT…

A brief evidence based review of diabetes after transplant

James Bushnell

April 2019

Agenda

• A brief background of diabetes after transplant

• Review latest consensus statement

History

• First described by Starzl in 19641

– Era of Steroids (up to 200mg/day Pred) and Aza

• Recognised as a clinical entity 19732

• No standard definition until 20033

1. Starzl TE et al. Surgery 1964;56:2962. Ruiz JO et al. Surgery 1973;73(5):7593. Davidson J et al. Transplantation 2003;75:SS3

Definition

• In line with WHO definition for diabetes1

– Fasting Glucose ≥7.0

– 2 hour glucose >11.1

• May include ADA definition2

– Symptoms+random glucose >11.1

– HbA1C >6.5%

1. World Health Ogranisation: Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia WHO Geneva

2. American Diabetes Association Diabetes Care 2011;34:S4

Incidence

• Varies for 2-53% in literature1

• 15.7% in retrospective data from SMH2

– Adult, non-diabetic patients

– Transplanted 9/04 to 10/07

– Diagnosed based on two glucose levels >11.1

1. Balla A. & Chobanian M. Curr Op Organ Transplant 2009;14:3752. Robinson J. Unpublished data

Pathophysiology

• Essentially as per Type II DM1

• But

– Insulin resistance can be found in 25% of non-obese, non diabetic controls2

– Loss of beta cell mass/function also needed3

1. World Health Ogranisation: Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia WHO Geneva

2. Reaven GM. Diabetes 1988;37:15953. Marchetti P et al. Nutr Metab Cardiovasc Dis 2006;16:S3

Similar to Type II DM

• Shared risk factors

• Similar pathophysiology

– Insulin resistance

– Failure of B cell compensation

• Similar complications

Different to Type II DM

• Transplant specific factors

– Transplant itself

– Kidney function

• Insulin clearance

• Gluconeogenesis

– Immunosuppression

Outcomes

• Poorer outcomes with respect to

– Patient survival (RR 1.8 vs. no NODAT)1

– Graft survival (RR 1.63 vs. no NODAT)1

– Cardiovascular events (RR 3.23 vs. no diabetes)2

– Serum creatinine3

– Acute rejection rates3

– Sepsis3,4

1. Kasike BL, et al. Am J Transplant 2003;3:1782. Hjelmaseth ,et al. Kidney Int 2006;69:5883. Kaposztas et al. Transplantation Proceedings, 2011;43:13754. Sumrani NB, et al. Transplantation 1991;51:343

Outcomes

• Similar risk of graft failure vs. ACR

• Significantly higher risk of death censored graft failure

• NODAT is more likely to lead to patient death with a functioning graft

Cole EH, et al. CJASN 2008;3:814

New Guidelines1. Change terminology from NODAT back to post-

transplant diabetes mellitus

2. Exclude transient post-transplant hyperglycaemia from PTDM diagnosis

3. Expand screening for PTDM – HbA1c and OGTT

4. Identify patients at risk of PTDM

5. Use best immunosuppression for patient and transplant survival regardless of PTDM risk

6. Use strategies for prevention and treatment beyond modification of immunosuppression

Sharif et al, Am J Trans 2014;14:1992-2000

What’s in a name?

• Initially ‘post-transplant diabetes’

• New-onset diabetes after transplant adopted in 2000s

• Diagnostic criteria ‘borrowed’ from WHO/ADA

Incidence of new diagnosis of diabetes in waitlisted renal transplant recipients

Woodward RS, et al. Am J Trans 2003;3:590

Exclude transient hyperglycaemia

• ‘Post transplant hyperglycaemia is ubiquitous’

– 92.5% of transplant recipients met criteria of in-patient hyperglycaemia

• 87% of these prescribed insulin

• ‘A formal diagnosis is best made when a patient is stable on maintenance immunosuppression with stable function and the absence of infection’

Chakkera et al, CJASN 2009;4:853

• But

– Published incidence of PTDM is 15-20%

– Post transplant hyperglycaemia is a RF for PTDM

– Any evidence of different outomes cf PTDM?

Park et al, Trans Proc 2015;47:555

Southmead Data

• 679 incident transplants

• Open ended follow-up

• Diabetes status according to available lab results

– 114 - Pre-existing DM

– 91 - PTDM (excluding results <45 days)

– 46 - Transient hyperglycaemia (<45 days)

– 428 - No hyperglycaemia

0.0

00.2

50.5

00.7

51.0

0

0 1000 2000 3000 4000Days

No Diabetes Post-Tx hyperglycaemia

PTDM Pre-existing DM

Survival post-transplant

Variable HR p value 95% Conf. Interval

Years of RRT 1.071 0.039 1.0034 - 1.143

Age 1.063 0.000 1.0395 - 1.086

No PKD 1.0 (Ref)

ADPKD 0.337 0.008 0.152 - 0.749

Pre-emptive 1.0 (Ref)

PD 2.417 0.017 1.170 - 4.995

HD 2.177 0.049 1.005 - 4.716

No CMV 1.0 (Ref)

CMV pre transplant 1.883 0.011 1.157 - 3.063

No Diabetes 1.0 (Ref)

Post Tx Hyperglycaemia 1.702 0.205 0.748 - 3.873

PTDM 1.118 0.738 0.582 - 2.146

Pre-existing DM 1.347 0.289 0.777 - 2.335

OGTT post-transplant

• 1571 transplant, 213 diabetes based on a week 10 OGTT

– 13% diagnosed by fasting glucose only

– 51% diagnosed by 2 hour glucose only

– 32% diagnosed by both

• OGTT remains the gold standard

Valderhaug et al, Transplantation 2009;88:429

HbA1c

• Adopted by WHO and ADA for diagnosis of diabetes in general population

• Not recommended <90days post transplant due to increased production/turnover of RBC

• HbA1c >48mmol/mmol correlates well with OGTT

– Sensitivity 88.9%

– Specificity 98.7%

Shabir et al, Transplant Int 2013;26:315

Afternoon glucose

• Comparison of 4pm Cap glucose vs OGTT vs HbA1c

– 6 weeks

• 46% elevated 4pm CBG

• 4% elevated HbA1c

• 12% elevated 2hPG

• 0% elevated FPG

Yates 2013 Transplantation 2013;96:726

Afternoon glucose

• Comparison of OGTT vs HbA1c

– 12 weeks



• 2% elevated FPG

– 12 months



• 2% elevated FPG

Yates 2013 Transplantation 2013;96:726

Screening

• Fasting glucose is rubbish

• HbA1c is good from 3 months

– Cut off 48mmol/mmol would miss 10% vs OGTT

– Cut off 40mmol/mmol would miss 7% vs OGTT

• OGTT (2hPG) remains the gold standard

Yates 2013 Transplantation 2013;96:726Shabir et al, Transplant Int 2013;26:315

Risk calculators

• Seven variables

– Age >50 years

– Planned steroid use

– Use of gout medication

– BMI >30kgm-2

– Fasting glucose >100mg/dL (mmol/L)

– Triglycerides >200,g/dL (mmol/L)

– Family history of Type II DM

Chakkera Diabetes Care 2013;36:2881

Steroids and PTDM risk

• Early withdrawal and steroid free regimens

• Acceptable transplant outcomes

• Usually driven by concerns over steroid SE

– Cardiovascular risk

– Diabetes risk

• Most replace steroids with higher doses of CNI

Pascual et al, Cochrane Database of Sytematic Reviews 2009;1:CD005632

Early withdrawal vs low dose maintenance

• RCT of Continued corticosteroid therapy (CCT) vs corticosteroid withdrawal (CSWD)

• No difference in PTDM rates, regardless of definition

• No increase in risk of PTDM in multivariate modelling

• Trend toward increase insulin use a higher HbA1c in CCT group

Pirsch et al Am J Trans 2015;15:1982

Calcineurin inhibitors

• Both cyclosporine and tacrolimus are diabetogenic

• DIRECT trial

– RCT of CsA v Tac

– 6 months FU

– OGTT between day 90 and 180

– PTDM in 26% with CsA, 34% Tac (p=0.046)

Prevention

• Current evidence…

Treatment

• Lifestyle

– First line treatment

– Single trial of 111 recipients

• Those with glucose intolerance got info, dietician, support

• Those with normal glucose tolerance got a leaflet

– Glucose tolerance improved by 15% in intervention group and worsened by 12% in controls

Sharif Transplantation 2008;85:353

PTDM specific treatment

• Metformin vs thiazolidinediones1

– Safe

– ‘No significant change in HbA1c from baseline’

• Rosiglitazone2

– Observational

– Safe and effective

1. Kurian et al, Endo Pract 2008;14:9792. Pietruck et al, Transplant Int 2005;18:483

PTDM specific treatment

• Repaglinide vs Rosiglitazone1

– Non-randomised, observational

– No changes in efficacy or tolerability

• Sitagliptin2

– Pilot, open label study

– Safe and effective

1. Turk et al, Am J Trans 2006;6:8422. Lane et al, Transplantation 2011;92:e56

Early insulin therapy?

• RCT of 50 consecutive renal transplant recipients

• Randomised to standard care or early basal insulin

• Treatment group received insulatard if evening CBG >140mg/dL (7.8mmol/L)

• Primary outcome – difference in HbA1c

• Secondary outcome – Prevalence of NODAT

Outcomes – Treated PTDM

Maintaining beta cell function

• Transplant causes insulin resistance and reduces beta cell function

• Hyperglycaemia and hyperlipidaemia are toxic to beta cells

• ?Beta cell protection by reducing glucose

• Similar to ‘honeymoon period’ seen in type I DM

Future studies

• SAPT-NODAT

– Larger scale trial of early insulin

• CSII-NODAT

– Insulin pump

• Trans-diab

– Metformin for IGT

• SGLT-2

Empagliflozin• SGLT2 inhibitor

• Placebo controlled RCT (single centre)– KTR >1yr with PTDM

– Empagliflozin 10mg vs placebo

• Outcomes– Reduction in HbA1c (-2mmol/mol vs

+1mmol/mol)

– Reduction in weight (-2.5kg vs +1kg)

– No change in transplant function

– No difference in adverse events

Halden et al. Diabetes Care March 2019 doi: 10.2337/dc19-0093

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I did not NODAT… · History •First described by Starzl in 19641 –Era of Steroids (up to...

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