POST-TRANSPLANT DIABETES MELLITUS

Transcription

1 POST-TRANSPLANT DIABETES MELLITUS Elias S. Siraj, M.D., FACP, FACE Associate Professor of Medicine Director, Clinical Endocrinology Program Director, Endocrinology Fellowship Temple University School of Medicine & Hospital Philadelphia, PA

2 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

3 Definition and Incidence of PTDM : Previous Studies Older studies lack uniform diagnostic criteria Newer studies: use ADA criteria for diagnosis References Definition of PTDM Pred/ AZA % Pred/ CSA % Pred/AZA/CSA % Bourdreaux et al 2 FBG > abnormal OGTT Meija et al 2 RBG > Roth et al 3 FBG > Yoshimura et al Requirement of insulin Sumrani et al 3 FBG > Hrick et al Requirement of insulin

4 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

5 Survival Free of Post-Transplant Diabetes with 95% Confidence Intervals (United Renal Data System) 100% Survival free of diabetes 95% 90% 85% 80% 75% 70% 65% 60% N= Months post-transplant Kasiske B, et al Am J Transplantation 2003; 3:178-85

6 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:

7 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: Hjelmesaeth J et.al. Diabetologia. 2004; 47:

8 Ethnicity and Risk for PTDM Incidence of PTDM (%) %* 21.3%* 3.6% Caucasian African American Hispanic Ethnicity *P<0.01 vs Caucasian. Sumrani et al. Transplantation. 1991;51:

9 Age and Risk for PTDM Incidence of PTDM (%) % 34% Age <45 Age >45 P<0.05 Boudreaux JP et al. Transplantation. 1987;44:

10 Hepatitis C and Risk for PTDM p = % Prevalence of Diabetes (%) % 13% 28% HCV +ve HCV -ve 0 Pre-transplant Diabetes Mellitus New-onset Diabetes after Transplantation asiske B, et al. Am J Transplantation 2003; 3: loom J Am Soc of Neph : ;

11 Cleveland Clinic Data Retrospective analysis Kidney Tx 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

12 Prevalence of Risk Factors for PTDM among Cases & Controls 80% P= % 60% 50% 40% P=0.04 P=0.18 CASE 30% CONTROL 20% 10% 0% P=0.16 Age>/40 BMI>/30 Minority HCV Ab + Abacan, Chinnappa, Wojtowicz, Braun, Siraj. 65th Scientific Sessions, ADA. June 2004, Orlando, Florida

13 PTDM and the Immunosuppressive Regimen Corticosteroids Calcineurin inhibitors Cyclosporine (CsA) Tacrolimus Other Azathioprine (AZA) Mycophenolate mofetil (MMF) Sirolimus

14 PTDM and Corticosteroids Observed in as many as 46% of renal transplant recipients receiving higher maintenance doses 1 Lower rates reported with relatively low steroid maintenance doses 2 Risk related to dose 3 Mechanism : Increased insulin resistance followed by relative insufficiency of insulin production 2 1 Gunnarsson R et al. Transplant Proc. 1979;XI: Weir MR et al. Am J Kidney Dis. 1999;34: Hjelmesæth J et al. Transplantation. 1997;64:

15 PTDM and Cyclosporine Steroid-sparing effect resulted in lower reported incidence of PTDM after introduction of cyclosporine 1 PTDM incidence of 3% to 14% with lower doses of cyclosporine and corticosteroids 1 Mechanism: Primary: diminished pancreatic secretory capacity 2 Secondary: insulin resistance 1 Weir MR et al. Am J Kidney Dis. 1999;34: van Duijnhoven EM et al. J Am Soc Nephrol. 2002;13:

16 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

17 PTDM and Tacrolimus Was expected to reduce incidence of PTDM secondary to reduction in dose of steroids Incidence of % reported in different studies Tends to be more reversible than CsA Mechanism: Primary: diminished pancreatic secretory capacity (> CsA) Secondary: insulin resistance

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

19 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

20 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:

21 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:

22 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 Another study Tetonico A, et.al. J Am Soc Nephrol 2005; 16: 3128 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

23 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)

24 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?

25 PTDM May Be a Predictor of Increased Risk for Graft Loss 4 years Graft Survival (%) % PTDM 82% No PTDM P<0.05 Roth D et al. Transplantation. 1989;47:

26 100 PTDM Is Associated With an Increased Risk of Infection Patients (%) % 17% 0 PTDM No PTDM P<0.05 Sumrani NB et al. Transplantation. 1991;51:

27 Patient Survival With and Without PTDM 1.0 Patient Cumulative Survival n = 978 No diabetes after transplantation (f/u 11.0 years) New-onset diabetes after transplantation (f/u 8.1 years) Years Jindal & Hjelmesaeth, Transplantation; 2000; 70: SS Other studies: Increased RR of death from CV ds 1.5-3

28 Occurrence of Complications Among Cases & Controls 80% P< % 60% P= % 40% 30% P=0.033 CASES WITH PTDM CONTROL 20% 10% 0% Rejections Infections P=0.08 acan, Chinnappa, Wojtowicz, Braun, Siraj. 65th Scientific Sessions, ADA. June 2004, lando, Florida

29 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:

30 Impact of Diabetes After Transplantation Diabetes after transplantation Graft function and survival Patient survival Proposed mechanisms Diabetic nephropathy Hypertension Low immunosuppressant doses Proposed mechanisms Increased infections Increased risk of CVD 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 :SS1-SS24.

31 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

32 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

33 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

34 Major Targeted Sites of Oral Drug Classes The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production. Liver Pancreas Beta-cell dysfunction Sulfonylureas Meglitinides DPP-4 inhibitors Muscle and fat Hepatic glucose overproduction Glucose level Insulin resistance Biguanides TZDs DPP-4 inhibitors Gut Glucose absorption Alphaglucosidase inhibitors Biguanides TZDs Biguanides DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med. 1999;131: Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:

35 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 > , CHF,Liver ds TZDs: CHF, edema states, liver ds

36 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

37 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

38 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 :SS1-SS24.

39 Goal of Therapy In short term (hospital) keep BG to < (max 180) In long term same as DM in general preprandial BG (< 110) bed time BG postprandial BG < 180 (< 140) HbA1c < 7% (< 6.5%)

40 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.