This report was reviewed for medical and scientific accuracy by Richard A. Mann, MD, MS, Associate Professor of Medicine, Microbiology and Molecular Genetics; Medical Director, Kidney/Pancreas Transplant Program, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Expert Commentary

Ali J. Olyaei, PharmD, BCPS, Associate Professor of Medicine, Division of Nephrology & Hypertension, Oregon Health Sciences University, Portland, Oregon

Obesity and diabetes are major causes of morbidity and mortality in the United States (U.S.).^1,2 The prevalence of obesity has increased by more than 75% since 1980.³ Moreover, data indicates that obesity and weight gain are associated with an increased risk of diabetes.^4,5 Overall, the direct costs of obesity account for approximately 9.4% of the U.S. health care expenditures,⁶ while the direct and indirect health care costs of diabetes have been estimated at $98 billion.⁷ The prevalence of obesity and diabetes among U.S. adults has been described as "epidemic".⁸

Post-transplant diabetes mellitus (PTDM) is a well-known but poorly-defined condition resulting from decreased insulin production, and/or increased insulin resistance. This disorder has been associated with the use of immunosuppression in the post-transplant period.⁹ In certain cases, PTDM has been associated with poor long-term patient outcomes, including increased mortality.¹⁰

Inconsistent definitions of PTDM in the literature have complicated the interpretation of reports of immunosuppression-related glucose intolerance and the comparison of various immunosuppressive regimens. Furthermore, the relationship between immunosuppressive therapies, PTDM, and clinical outcome are complicated by a myriad of other confounding factors, including baseline patient character-istics, comorbid disease states, and concomitant drug therapies. As a result, the true risk of PTDM, as well as its etiology, may be distorted by a failure to distinguish between patients with new-onset diabetes or those with an exacerbation of a pre-existing condition.

The purpose of this Transplantation Express Report™ is to examine the impact of obesity on the development of PTDM.

Obesity and Diabetes in the General Population

In 2001, the prevalence of obesity (body mass index (BMI)≥30 kg/m2) was 20.9% among U.S. adults,¹¹ compared to 19.8% in 2000 and 12.0% in 1991,^8,12 reflecting a 74% increase from 1991 (Table 1). Perhaps even more alarming, the incidence of extreme/morbid obesity (BMI≥40 kg/m²) was approximately 2.3%, compared to 2.1% in 2000 and 0.9% in 1991. Approximately 60% of U.S. adults were considered overweight (BMI≥25-29.9 kg/m²), compared with 45% in 1991. Similarly, the incidence of diagnosed diabetes (self-report) increased from 4.9% in 1990¹³ to 7.3% in 2000⁸ to 7.9% in 2001,¹¹ a 61% increase. Approximately 3.4% of U.S. adults were both obese and had diabetes in 2001,⁸ compared with 1.4% in 1991.

Both BMI and weight gain are major risk factors for the development of diabetes.^14,15 In a national sample of adults, for every 1-kg increase in measured weight, the risk of diabetes increased by 4.5%.⁴ Both obesity and diabetes are largely preventable. Studies have demonstrated that changes in lifestyle are effective in preventing obesity and diabetes in selected groups of adults who are at high risk.^16-18

Obesity and the Renal Transplant Patient

There are limited data on the effect of obesity on the renal transplant recipient. Recent evidence indicates that the majority (60%) of recipients are overweight or obese at the time of transplantation.¹⁹ Between 1990 and 2001, the proportion of obese transplant recipients rose by 93.1%, grossly similar to that in the general population. Conversely, the proportion of recipients with lower BMI fell by approximately 50% (Table 2).

Estimates of the incidence of PTDM vary widely based on the definition employed and the length of time studied. A recent report summarizing data from the U.S. Renal Data System (USRDS) (N = 11,569), estimated that the cumulative incidence of PTDM was 9.1% (95% Confidence Interval (CI), 8.6-9.7%), 16% (95% CI, 15.3-16.7%), and 24% (95% CI, 23.1-24.9%) at 3, 6, and 36 months post-transplant, respectively.²⁰ Approximately 24% of patients (n = 2,785) had received tacrolimus as their initial immunosuppressive therapy and 69% (n = 8,016) had received cyclosporine. The relative risk (RR) of PTDM associated with tacrolimus versus no tacrolimus was 1.53 (95% CI, 1.29-1.81; P<.0001). Interestingly, while PTDM was associated with increased risk of graft failure (RR 1.63, 95% CI, 1.46-1.84; P<.0001), tacrolimus therapy was associated with reduced risk of graft failure (RR 0.65, 95% CI, 0.59-0.83; P<.0001) and death (RR 0.65, 95% CI, 0.50-0.84; P<.001). This retrospective analysis likely overestimated the true incidence of PTDM as it did not account for patients with underlying disorders of glucose metabolism or patients who experienced reversal of diabetes over time as no reliable follow-up data were collected. Several recent comparative trials of immunosuppressive regimens have reported lower PTDM incidence rates (2% to 8% over periods of 6 months to 2 years) and have failed to demonstrate an increased incidence of PTDM in patients treated with tacrolimus.^21-23

Recognized Risk Factors for Post-transplant Diabetes Mellitus

While it is impossible to predict with certainty which patients will develop PTDM, several patient characteristics have consistently been associated with increased risk. These include increased age,^10,20,24 African-American^{10,20,22,24,25} or Hispanic descent,²⁰ and increased body weight.^10,20,24 Associations between male gender, hepatitis C infections, and human leukocyte antigen (HLA) mismatches and PTDM have also been described.

The interactions between these patient characteristics, immunosuppressive therapy, and the development of PTDM remain to be defined. Several of these characteristics are associated with increased risk of diabetes in the general population (eg, increased age, obesity, and African-American or Hispanic descent²⁶). Therefore, it is not known if patients with these characteristics would have gone on to develop diabetes in the absence of transplantation or if transplantation and immunosuppressive therapy contributed to, or shortened the time-course of the development of PTDM.

Relationship between Pre-transplant Obesity and Post-transplant Diabetes Mellitus

Obesity has been associated with increased surgical complications, increased cardiovascular mortality, and indeed, increased overall mortality in renal transplantation patients. Data regarding out-comes in patients who are obese pre-transplant are contradictory. A recent retrospective analysis examined the association between pre-transplant obesity and the incidence of PTDM.²⁷ Additional outcomes included non-fatal cardiovascular events and patient and graft survival. A total of 608 adult renal transplant patients were followed for at least 5 years. Mean BMI at transplantation was 24.98 kg/m² ±0.41 with no significant difference in BMI between diabetic and non-diabetic patients. Approximately 56% of recipients had a BMI≥25 kg/m², 29.8% between 25 kg/m² and 30 kg/m², and 14.6% had a BMI >30 kg/m². At 3 months post-transplant, 32.2% of patients were obese (BMI >30 kg/m²). The adjusted risk of PTDM within 5 years post-transplant increased by 9.6% per unit increase in BMI (P = .002). Patient survival was significantly worse in obese patients (P = .005); however, differences in graft survival did not reach statistical significance (P = .07). Investigators concluded that obesity at the time of renal transplantation was a significant risk factor for non-fatal cardiovascular events, PTDM, and patient death. Further follow-up is necessary to determine if pre-transplant obesity is associated with worse graft survival.

Impact of Immunosuppressive Agents on Post-transplant Diabetes Mellitus

The calcineurin inhibitors cyclosporine and tacrolimus have greatly improved short-term outcomes in renal transplant patients; however, the relative propensity of these agents to cause disorders of glucose metabolism such as PTDM continues to be the subject of much study and debate.

A recent retrospective analysis by First and colleagues analyzed data from 435 kidney recipients at 5 transplant centers and compared the incidence of PTDM among patients treated with tacrolimus-based (n = 283) or cyclosporine-based (n = 149) regimens over a mean follow-up period of 561 days (range, 201 to 1,336 days).²¹ Secondary immunosuppressive agents included mycophenolate mofetil (77.9%), prednisone (92.0%), azathioprine (1.1%), sirolimus (4.4%), and everolimus (3.0%). Doses of both calcineurin inhibitors decreased over time and mean trough blood levels of tacrolimus and cyclosporine at latest follow-up were 10.1 ng/mL and 221 ng/mL, respectively.

Of the patients who did not have a history of diabetes prior to transplantation (n = 369), 18 (4.9%) developed PTDM (defined as requiring insulin to normalize blood glucose) and 23 (6.2%) developed hyperglycemia (defined as requiring oral anti-diabetic agents to normalize blood glucose). Whereas more patients developed PTDM while on tacrolimus-based regimens (14/245, 5.7%) than on cyclosporine-based regimens (4/121, 3.3%), this difference was not statistically significant (P = .453). Similar proportions of patients receiving tacrolimus (n = 15, 6.1%) and cyclosporine (n = 8, 6.6%) developed hyperglycemia (P = .999). Furthermore, multivariate risk analysis demonstrated that the only significant risk factor for the development of PTDM was the absence of an antiproliferative agent (odds ratio 3.56; P<.01).

Management of Post-transplant Weight Gain

Early intensive dietary advice and follow-up have been shown to be effective in controlling weight gains observed in the first year post-transplant. In a study by Patel of 33 transplant recipients,²⁹ weight gain and BMI were evaluated at 4 months and 1 year post-transplant. Patients were divided into 2 groups—one received intensive, individualized dietary advice in stages for the first 4 months post-transplant, with no advice for the next 8 months and the second received no dietary advice or follow-up for the 12 months post-transplant. Both groups had functioning grafts (serum creatinine <2.2 mg/dL) and similar triple immunosuppressive therapy (prednisolone, cyclosporine, and azathioprine).

The group receiving dietary advice showed no significant difference in weight gained and BMI at 4 months follow-up post-transplant compared with baseline. However, there was a significant difference in weight gain and BMI at 12 months post-transplant compared with 4 months post-transplant (P = .002, P = .002, respectively). Analysis between groups showed a significantly lower weight gain in favor of the group that received dietary advice at both 4 and 12 months post-transplant (P = .01, P = .01, respectively) and significantly lower BMI at 4 and 12 months post-transplant (P = .003, P = .006, respectively). At 12 months post-transplant, the mean weight gain in the group receiving dietary advice was 5.5 kg per patient compared with a mean of 11.8 kg per patient in the group that received no dietary advice.

Dietary advice should be an important part of post-transplant treatment. Dietary intervention has also been shown to improve lipid profiles in renal transplant recipients.³⁰

Management of Post-transplant Diabetes Mellitus

It is widely accepted that diabetes is associated with negative patient outcomes, including effects on renal and cardiovascular health.²⁶ Therefore, stringent management of blood glucose levels is recommended for all patients with diabetes, regardless of cause.

An algorithm developed by First and colleagues for the management of PTDM recommends frequent monitoring and use of standard anti-diabetic therapies for blood glucose control.²¹ In this algorithm, oral sulfonylureas or thiazolidinediones are recommended for patients who develop hyperglycemia (defined in algorithm as fasting blood glucose 160-250 mg/dL) and insulin for those who develop diabetes (defined in algorithm as fasting blood glucose >250 mg/dL).

Patients should be monitored frequently to ensure that blood glucose levels are maintained within the optimal range. Further-more, continued monitoring should allow for early detection of reversal of PTDM and the opportunity to discontinue anti-diabetic therapy. Switching calcineurin inhibitors should only be considered in patients who require extreme measures for glucose control (eg, hospitalization) and for whom the risk of rejection is low. Prior to switching calcineurin inhibitors, the dose of all immunosuppressive therapies should be optimized (prednisone dose of <10 mg/day and cyclosporine trough levels <200 ng/mL). Doing so may improve glucose control and eliminate the need to change therapies. In patients with recognized risk factors for the development of PTDM, tacrolimus troughs should be maintained below 15 ng/mL to minimize their risk of developing PTDM.³¹

References

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Disclosure
Richard A. Mann, MD, MS
No significant relationships to disclose.

Ali J. Olyaei, PharmD, BCPS
Grant/Research Support-Fujisawa Healthcare, Inc., Pfizer, Roche, Wyeth Speakers Bureau-Fujisawa Healthcare, Inc., Pfizer, Roche, Wyeth

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Fujisawa Healthcare, Inc.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Transplantation Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Transplantation Express Report™ was made possible through an educational grant from Fujisawa Healthcare, Inc.

© 2004 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education