Cardiovascular diseases are the major cause of death in renal transplant recipients with a functioning graft, accounting for approximately 50% of all-cause mortality (1, 2). New-onset diabetes after transplantation (NODAT) is a major contributor to the burden of cardiovascular disease (1, 3). Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are recognized risk factors for diabetes and cardiovascular disease in both general (4–6) and transplant recipient (7–9) populations. Impaired glucose tolerance, which reflects abnormal postprandial glucose metabolism, has a higher risk for cardiovascular disease and diabetes than IFG (4, 10–16), which represents normal postprandial glucose metabolism. Thus, a targeted approach to the prediabetic transplant recipient may attenuate the development and progression of postprandial hyperglycemia and help reduce the cardiovascular morbidity and mortality associated with abnormal glucose metabolism.
The International Consensus Guidelines (17) issued by an expert panel on NODAT recommend nonpharmacologic therapy as first-line management for patients with NODAT, in line with guidance from the American Diabetes Association (18). Lifestyle modification (dietary changes, weight loss, and physical exercise) has been the mainstay for initial management of diabetes for decades in the general population. Lifestyle modification has also been shown to delay the onset of diabetes in nontransplantation subjects with abnormal postprandial glucose metabolism such as IGT (19–21). The NODAT guidelines also recommend intensive preventative strategies in renal transplant recipients who are diagnosed with IGT, although routine use of an oral glucose tolerance test (OGTT) is not advocated (17). No data show that lifestyle modification has any benefit in delaying diabetes mellitus in patients with an IFG. Although a similar benefit might be extrapolated in transplant recipients, there are no studies to show lifestyle intervention prevents or delays the onset of NODAT for transplant recipients with IGT. Because of the presence of both traditional and transplantation-specific risk factors for hyperglycemia after transplantation (22–24), the feasibility and efficacy of lifestyle modification specifically for this population would be important to validate.
The authors’ previous study highlighted the benefit of using an OGTT to diagnose abnormal glucose metabolism in transplant recipients (25). The hypothesis tested in this study is that the patients who were diagnosed with abnormal postprandial glucose metabolism could attenuate their glycemic dysregulation with intensive lifestyle modification. The aim of this prospective study was to assess the impact of lifestyle modification in renal transplant recipients with NODAT and impaired glucose tolerance and to contrast this with the natural history of glucose metabolism in normal glucose tolerant patients.
MATERIALS AND METHODS
The original study was performed between August 2005 and April 2006 and involved 122 renal transplant recipients (6 months and later after transplantation and no diagnosis of prior posttransplantation diabetes mellitus) who underwent an OGTT as part of a risk stratification model. They were screened for a fasting glucose between 5.6 and 6.9 mmol/L and were eligible for this original study if they fulfilled this criteria on two separate occasions from their previous three measurements (25). The results revealed 40 patients with undiagnosed glucose intolerance: 12 patients had NODAT and 28 had IGT. Four renal transplant recipients diagnosed with NODAT were commenced immediately onto oral hypoglycemic agents because of their constellation of cardiovascular risk factors. The remaining 118 patients were invited to enroll in the new study to prospectively assess change in glycemic status, which was approved by the South East Wales Local Research Ethics Committee.
One hundred fifteen patients gave informed consent and were split into two groups depending on their glycemic status:
- Group 1: Glucose intolerance group (n=36) was made up of patients with abnormal postprandial glucose metabolism and comprised NODAT (n=8) and IGT (n=28). This group received aggressive lifestyle modification advice which consisted of dietician referral, graded exercise program, and weight loss advice. Each patient diet was reviewed by a dietician and healthy eating advice given based on guidelines issued by Diabetes UK (26). The guidelines recommended a diet containing less fat and more fiber, based on a meal framework of 50% carbohydrate, 25% protein (meat, fish, beans), and 25% fiber (fruit and vegetables). Graded exercise programs were established to increase physical activity (minimum 2 hr of endurance exercise such as walking, jogging, and swimming required per week). Patients were advised to keep dietary and exercise diaries to monitor compliance with initiated changes and were followed up by the dieticians to monitor progress and reinforce the advice. They were followed up by investigating physicians at routine clinic visits. Any subject who received modification of immunosuppression (for example, steroid minimization or withdrawal) was removed from any further analysis in this article.
- Group 2: Normal glucose tolerance group (n=79) was made up of patients with normal postprandial glucose metabolism and comprised normal OGTT (n=58) and IFG (n=21). They were counseled about the risks of glucose intolerance and received leaflets with lifestyle modification advice. The leaflets included advice on healthy eating, exercise, and the importance of weight loss. However, there was no dietician referral or focused exercise and weight loss monitoring program. Follow-up was at routine clinic visits only, where the lifestyle modification advice was reinforced.
After minimum 6 months (range, 6–12 months), both groups underwent a repeat OGTT to assess any change in glycemic status. The benefit of aggressive lifestyle modification in the glucose intolerant group (group 1) was compared with the natural evolution of glycemic regulation in the normal glucose tolerance group (group 2).
Demographic data were collected at baseline for each individual participant to document age and sex. The following data were collected at baseline and at follow-up. Weight and height were measured to the nearest 0.1 kg and 1 cm, respectively. Body mass index was calculated as weight in kilograms divided by height in meters squared. Estimated glomerular filtration rate was calculated using the Modified Diet and Renal Disease formula. Arterial blood pressure was measured using a standard manual mercury sphygmomanometer with the patient in a seated position with the mean of three readings recorded. Resting heart rate was recorded with the third blood pressure measurement. Physical activity was evaluated by targeted questioning by the investigating physician, assessing time spent on weekly exercise. Resting heart rate was measured at the beginning and end of the study period as a surrogate endpoint for exercise intensity (27).
The methodology of the OGTT has been previously described (25). Fasting blood samples were taken for glucose and lipids in addition to routine clinic bloods after an overnight 12-hr fast. Patients were then administered 75 g of glucose (113 mL of Polycal [Nutricia Clinical Care, England]) with postprandial samples taken 2 hr after administration of glucose. The results of the test were classified by WHO guidelines (28) as shown in Table 1.
Statistical analysis was performed using standard software (SPSS Version 11, Mac version, Chicago, IL). Normality of data was assessed using the Kolmogorov-Smirnov tests. Paired sample t test and Wilcoxon signed rank test, for parametric and nonparametric data, respectively, were used to compare the means of two variables from a single group. Comparison of data between groups was made using unpaired Student’s t tests and the Mann-Whitney test for parametric and nonparametric data, respectively. Categorical data were analyzed using Pearson’s or Spearman’s test as appropriate. A P value <0.05 was considered significant in the statistical analysis.
All 115 renal transplant recipients who gave informed consent completed the prospective study and had a follow-up OGTT. The mean time from baseline to follow-up OGTT was 8.2 months with a median of 9 months. Four patients from group 1 underwent steroid weaning or withdrawal in an attempt to alleviate their glucose intolerance and were therefore excluded from further analysis, leaving a cohort of 111 patients. Table 2 outlines the baseline demographics and clinical and biochemical parameters comparing the two groups.
In group 1, 44% received tacrolimus at baseline compared with 42% at follow-up. Average tacrolimus levels were 8.8 and 8.4 μg/L at baseline and follow-up, respectively. Twenty-seven percent received steroids at baseline (average dose, 6.2 mg) compared with 27% at follow-up (average dose, 6.2 mg). Sixty-five percent received beta-blockers at baseline compared with 63% at follow-up. The average dose of antihypertensives at baseline was 2.1 compared with 2.2 at follow-up. None of these changes was of statistical difference.
In group 2, 61% of patients received tacrolimus at baseline compared with 58% at follow-up. Average tacrolimus levels were 8.6 μg/L at baseline and 8.1 μg/L at follow-up. Twenty-two percent of group 2 patients received steroids at baseline (average dose, 6.5 mg) compared with 20% at follow-up (average dose, 6.3 mg). Fifty-seven percent of the group received beta-blocker therapy at baseline compared with 58% at follow-up and the average number of antihypertensive agents was 1.9 compared with 2.0 at follow-up. As in group 1, there was no statistical difference in these changes.
In group 1, compliance with the aggressive lifestyle modification was excellent with 100% of subjects completing longitudinal reviews with the dieticians. Ninety-four percent (n=30) maintained a dietary diary, and 88% (n=28) maintained an exercise diary throughout the study, both of which had satisfactory documentation as deemed by the dietician team. Both diet and exercise were analyzed before the intervention began and at the end of the study period.
Lifestyle Modification in Transplant Recipients With Glucose Intolerance
The change in glycemic status after lifestyle modification in group 1 are shown as individual subgroups highlighting NODAT (Fig. 1A) and IGT (Fig. 1B) patients individually.
Figure 1(A) shows seven renal transplant recipients who were newly diagnosed with NODAT, and not immediately requiring oral hypoglycemic agents, underwent lifestyle modification. On repeat analysis, three patients remained with NODAT but two improved their status to IGT and two achieved normal glucose tolerance.
Figure 1(B) highlights 25 transplant recipients with IGT who underwent lifestyle modification. One patient deteriorated to NODAT and 13 remained with IGT on repeat testing. However, an improvement in glycemic status to normal glucose tolerance was achieved in 11 patients.
Change in Clinical and Biochemical Parameters in Group 1
Table 3 outlines change in parameters observed in group 1 over the prospective period.
In these group 1 patients treated with active lifestyle modification, there was a significant reduction in 2-hr postprandial glucose levels from 10.2 to 8.7 mmol/L (15% reduction, P=0.012). There was a dramatic increase in the percentage of patients achieving more than 2 hr of exercise per week compared with baseline, which was of strong statistical significance (28% vs. 71%, P<0.001). This coincided with a nonsignificant trend toward a decrease in resting heart rate over the study period from 84 to 81 beats per minute (P=0.087). All other parameters had nonsignificant changes.
Effect of Lifestyle Advice in Transplant Recipients With Normal Glucose Tolerance
Group 2 consisted of 79 renal transplant recipients with normal glucose tolerance that received advice regarding lifestyle modification and the risk of developing IGT and NODAT. The purpose of this group was to assess the natural evolution of glucose metabolism in renal transplant recipients with time and this is shown in Figure 2.
Of the group of 79 patients, 67 remained with normal glucose tolerance after their repeat OGTT. However, 10 patients had deteriorated to IGT and 2 deteriorated to NODAT at the end of the study period.
Change in Clinical and Biochemical Parameters in Group 2
Table 4 outlines the observed changes in group 2 patients who received lifestyle advice with leaflets only.
As opposed to the active lifestyle modification group, there was a significant increase in 2-hr postprandial glucose levels in group 2 patients over the prospective study period from 5.9 to 6.6 mmol/L (12% increase, P=0.001). This is likely to explain the deterioration of glycemic status observed in 17% of group 2 renal transplant recipients. There was a significant increase in the percentage of patients taking more than 2 hr of exercise per week (42% vs. 49%, P=0.014) although this was less marked than in group 1. There was no improvement in resting heart rate between baseline and follow-up. No significant difference was observed in any of the other clinical or biochemical parameters.
This study is the first to provide evidence that lifestyle modification in renal transplant recipients with abnormal glucose metabolism can attenuate and, in some cases, reverse the progression of glycemic dysregulation. NODAT is becoming a major clinical burden after transplantation (29). Thus, strategies which can address this growing problem should be encouraged. Lifestyle modification is often overlooked or neglected by clinicians in favor of progressing directly to hypoglycemic therapy and this study reinforces the guidance from the American Diabetes Association (18) and International Consensus Guidelines on NODAT (17) that lifestyle intervention is an important and crucial part of the care required for managing glucose intolerant individuals.
In the general population, studies have shown lifestyle modification can have beneficial effects on the diabetogenicity of an individual, especially in patients with IGT who are at high risk of developing diabetes (5, 10, 13, 16). Tuomilehto et al. (20) showed how the cumulative incidence of diabetes in a lifestyle intervention group was 11% compared with 23% in a control group of similar characteristics, resulting in a 58% reduction in the risk of diabetes (P<0.001). In another study to support these findings, Pan et al. (19) showed that diet, exercise and diet-plus-exercise intervention was associated with reductions of 31% (P<0.03), 46% (P<0.0005), and 42% (P<0.005), respectively in the risk of developing diabetes compared with the control group.
Although the evidence for lifestyle intervention in the general population is well established, no validation of this approach exists among the transplant recipient population. The transplant recipient population lacks evidence of the benefits of lifestyle modification and also lacks any comparative evidence of the efficacy of several oral hypoglycemic agents. While some of the new hypoglycemic agents have been studied in renal transplant recipients, such as repaglinide (30) and rosiglitazone (31), the older and more commonly used hypoglycemic agents have not been assessed in this particular population. This should reinforce the importance of lifestyle modification in transplant recipients as successful attenuation or reversal of abnormal glucose metabolism could prevent or delay the onset of NODAT and initiation of hypoglycemic therapy.
In this study, changes in glycemic state were almost exclusively caused by the changes in 2-hr postprandial glucose levels, whereas fasting glucose is primarily determined by a feedback loop mechanism between the liver and pancreatic beta cell, postprandial glucose is dependent on glucose uptake by insulin-sensitive tissues and is more influenced by insulin resistance (32–34). Insulin resistance is a pathological state in which target cells fail to respond to ordinary levels of circulating insulin (35, 36). Obesity, inadequate diet, and physical inactivity all contribute to decreasing insulin sensitivity (35, 37). Lifestyle modification, by targeting these major causes of insulin resistance, can successfully lower postprandial glucose levels and change an individuals’ glycemic state. This is an important clinical benefit as postprandial glucose has a strong linear correlation with cardiovascular and all-cause mortality (12–15).
Perhaps surprisingly, change in postprandial glucose metabolism had no correlation with change in weight in this study. The inability to detect any significant weight change may reflect either too short a time period to assess any significant difference or a lack of study numbers to adequately answer the question. In the numerous studies looking at lifestyle modification (diet, weight loss, physical exercise) in the general population, none has been designed to show the relative contribution of each individual component to the reduction in risk of diabetes. Thus it can be argued that weight loss alone should not be the priority, but careful and targeted attention on overall lifestyle modification should be encouraged.
This postulation is supported by Boule et al. (38) who conducted a meta-analysis of 14 controlled clinical trials assessing the effects of exercise on glycemic control and body mass in type 2 diabetics. They concluded that increased physical activity was associated with significantly improved glucose metabolism in exercise groups compared with that in control groups, but without a significant change in body mass. This conclusion would concur with the results of this study, which showed a dramatically increased exercise rate in group 1 compared with that in group 2. This was supported by a decrease in resting heart rate in group 1, although this failed to reach statistical significance. The finding that exercise does not need to reduce body weight to have a beneficial impact on glucose metabolism is clinically important. Patient compliance with exercise may decline if they do not see any objective evidence of beneficial change such as weight reduction. Exercise training decreases hepatic and muscle insulin resistance and increases glucose disposal through numerous mechanisms, which would not necessarily be associated with weight change (38, 39). Suggested mechanisms include increased postreceptor insulin signaling, increased glucose transporter and messenger RNA and increased activity of glycogen synthase and hexokinase (39).
The limitations of this study include the inability to accurately assess compliance with the dietary and exercise modifications made in the intervention patients. Assessment of exercise was subjective and could have led to an inaccurate evaluation of an individuals’ physical activity, although the use of resting heart rate as a surrogate for physical intensity was used as a clinical endpoint. This study also attempted to quantitatively assess patient compliance with these lifestyle modifications by using diet and exercise diaries, which were independently reviewed by the dieticians. There is a lack of comparative analysis in this study by having two different groups receiving two different interventions (high-risk group received intensive intervention and a low risk group served as the control), which could directly or indirectly affect motivation levels. However, it would have been unacceptable to use any of the high-risk patients as controls because it would be contrary to published guidelines (17, 18) regarding appropriate management of glucose intolerance. The purpose of this article was to assess the efficacy of widely published best-practice guidance on how to manage both glucose tolerant and glucose intolerant renal transplant recipients, which has never been previously validated. Finally, this article outlines the feasibility of using a more intensive approach; however, the cost-effectiveness of this strategy was not assessed.
Overall these results are the first to show that aggressive lifestyle modification is an effective and important line of management in renal transplant recipients with NODAT or IGT to attenuate and/or regress abnormal glucose metabolism. All renal transplant recipients should have regular assessment of their glycemic status by means of an OGTT and active lifestyle modification initiated in glucose intolerant patients. Normal glucose tolerant patients should not be overlooked from continued clinical vigilance and may benefit from a more intensive approach as a preventative measure. NODAT is a major clinical burden and this simple yet highly effective strategy will help tackle one of the biggest challenges in the long-term management of renal transplant recipients.
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